Processes for preparing calixarenes

ABSTRACT

This invention relates to a process for preparing a calixarene compound by reacting a phenolic compound and an aldehyde in the presence of at least one nitrogen-containing base as a catalyst to form the calixarene compound. The invention also relates to processes for high-yield, high solid-content production of a calixarene compound, with high selectivity toward a high-purity calix[8]arene compound, without carrying out a recrystallization step.

This application is a continuation of U.S. patent application Ser. No.16/271,499, filed Feb. 8, 2019, which claims priority to U.S.Provisional Application No. 62/628,472, filed on Feb. 9, 2018, which isherein incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention generally relates to a process for preparing calixarenes.

BACKGROUND

Calixarenes have found widespread uses as complexation hosts and asframeworks for the construction of more complex structures. Calixarenecompounds are typically synthesized by using an alkaline base, such assodium hydroxide, as a catalyst. To obtain a high calixareneconcentration in the product, the reaction system was often timesdiluted. Additionally, to obtain a high purity and high selectivity of acalixarene compound having a particularly ring size, recrystallizationof the obtained cyclic reaction product was typically necessary. Forinstance, the procedure reported by Munch et al., in Organic Syntheses68:243-46 (1990), describes the synthesis ofpara-tert-butylcalix[8]arene in the presence of sodium hydroxide as thecatalyst with a yield of 60-65%. In the Munch process, the synthesis wasconducted in an excessive amount of xylene, and to obtain a high purityof para-tert-butylcalix[8]arene, the crude cyclic reaction product,containing about 10-13% of other calixarene oligomers (e.g.,calix[4]arene and calix[6]arene), was recrystallized. This procedure wasdescribed as the best-yielding, state of art synthetic procedure forpreparing a calix[8]arene compound according to C. David Gutsche,Calixarenes, An Introduction (The Royal Society of Chemistry, Cambridge,UK, 2^(nd) Ed. 2008), pages 30-31; and Placido Neri et al., Calixarenesand Beyond (Springer International Publishing AG Switzerland, 2016),pages 142-143.

A similar procedure for synthesizing para-tert-butylcalix[8]arene wasalso described in U.S. Pat. No. 5,736,289 to Sukata et al., as aone-step synthesis, using an alkaline base catalyst, such as potassiumhydroxide, in an excessive amount of xylene. In Sukata, although theyield of a white powder (the white powder was identified as cycliccompounds mainly containing para-tert-butylcalix[8]arene) was 85%, theyield of para-tert-butylcalix[8]arene in the white powder was unknown.Other cyclic oligomers besides para-tert-butylcalix[8]arene may havebeen present in the powder; moreover, Sukata noted that some of thecyclic compounds in the white powder were metallized with potassium.Thus, the procedure disclosed in Sukata also does not provide a highyield, high purity, and high selectivity synthesis of a calix[8]arenecompound.

Therefore, there remains a continuing need in the art to develop ahigh-yield process to prepare calixarene compounds, in particular acalix[8]arene compound, with a high purity and high selectivity, withoutthe need for more complicated purification steps, such as arecrystallization step. This invention answers that need.

SUMMARY OF THE INVENTION

One aspect of the invention relates to a process for preparing acalixarene compound, comprising reacting a phenolic compound and analdehyde in the presence of at least one nitrogen-containing base as acatalyst to form the calixarene compound.

In certain embodiments, the nitrogen-containing base is a stericallyhindered amine or a tetraalkyl ammonium hydroxide.

In certain embodiments, the nitrogen-containing base is an amidinecompound having the formula of

wherein R₁, R₂, R₃, and R₄ are each independently H, alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; or any two or more of R₁, R₂, R₃,and R₄ can be bonded together to form a five- to nine-membered ringstructure. In one embodiment, the amidine compound is selected from thegroup consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,2-dimethyl-1,4,5,6-tetrahydropyrimidine,1-ethyl-2-methyl-1,4,5,6-tetrahydropyrimidine,1,2-diethyl-1,4,5,6-tetrahydropyrimidine,1-n-propyl-2-methyl-1,4,5,6-tetrahydropyrimidine,1-isopropyl-2-methyl-1,4,5,6-tetrahydropyrimidine,1-ethyl-2-n-propyl-1,4,5,6-tetrahydropyrimidine, and1-ethyl-2-isopropyl-1,4,5,6-tetrahydropyrimidine.

In certain embodiments, the nitrogen-containing base is a guanidinecompound having the formula of

wherein R₂′, R₃′, R₄′, and R₅′ are each independently H, alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or any two or more ofR₂′, R₃′, R₄′, and R₅′ can be bonded together to form a five- tonine-membered ring structure. In one embodiment, the guanidine compoundis selected from the group consisting of 1-methylguanidine,1-n-butylguanidine, 1,1-dimethylguanidine, 1,1-diethylguanidine,1,1,2-trimethylguanidine, 1,2,3-trimethylguanidine,1,3-diphenylguanidine, 1,1,2,3,3-pentamethylguanidine,2-ethyl-1,1,3,3-tetramethylguanidine,1,1,3,3-tetramethyl-2-n-propylguanidine,1,1,3,3-tetramethyl-2-isopropylguanidine,2-n-butyl-1,1,3,3-tetramethylguanidine,2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,2,3-tricyclohexylguanidine,1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD),7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),7-ethyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-n-propyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-isopropyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-n-butyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-isobutyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-tert-butyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-cyclohexyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-n-octyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-2-ethylhexyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, and7-decyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

In certain embodiments, the nitrogen-containing base is a tetraalkylammonium hydroxide. For instance, each alkyl moiety in the tetraalkylammonium hydroxide may be independently C₁ to C₆ alkyl.

In certain embodiments, the nitrogen-containing base is a stericallyhindered primary amine, a sterically hindered secondary amine, asterically hindered tertiary amine, a morpholine compound, an imidazolecompound, a pyridine compound, a triamine compound, or anamino-containing ether compound.

In certain embodiments, the phenolic compound is phenol, an alkylphenol, or an arylalkyl phenol. In one embodiment, the phenolic compoundis a para-C₁-C₂₄ alkyl phenol, such as a para-tert-C₄-C₁₂ alkyl phenol.In one embodiment, the phenolic compound is benzyl phenol or cumylphenol.

In certain embodiments, the aldehyde is formaldehyde orparaformaldehyde.

In certain embodiments, the molar ratio of the phenolic compound to thealdehyde ranges from about 1:1.5 to about 1.5:1, and the molar ratio ofthe phenolic compound to the nitrogen-containing base ranges from about200:1 to about 20:1.

In certain embodiments, the reaction is carried out in the presence ofan organic solvent. In one embodiment, the reaction is carried out in ahighly concentrated reaction system, wherein the mass ratio of thephenolic compound to the organic solvent is no less than 0.25:1.

In certain embodiments, the reaction is carried out under refluxconditions. In certain other embodiments, the aldehyde isparaformaldehyde and the reaction is carried out without reflux.

In certain embodiments, the process further comprises heating thereaction mixture at an elevated temperature of 140° C. to 180° C. for atime period of 4 hours or longer to remove water from the reactionmixture.

In certain embodiments, the process is carried out in a one-stepreaction and does not include a recrystallization step. In oneembodiment, the process further comprises filtrating the reactionproduct and drying the filtrated reaction product, thereby producing acalixarene compound containing at least 95% calix[8]arene. In oneembodiment, the process further comprises washing the reaction productwith an organic solvent to remove free phenolic monomers. The processmay further comprise filtrating the washed reaction product and dryingthe filtrated reaction product, thereby producing a calixarene compoundwith a free phenolic monomer content of about 0.5% or lower.

Embodiments of the invention also include a phenolic oligomercomposition prepared by the process described in this aspect of theinvention and in any of the above embodiments of this aspect of theinvention.

Another aspect of the invention relates to a process for a high-yield,high solid-content production of a calixarene compound. The processcomprises reacting a phenolic compound, an aldehyde, and a base catalystin the presence of an organic solvent, in a highly concentrated reactionsystem. The mass ratio of the phenolic compound to the organic solventin the reaction system is no less than 0.25:1. The process produces acalixarene-containing product having at least 50% solids.

In certain embodiments, the nitrogen-containing base is a stericallyhindered amine or a tetraalkyl ammonium hydroxide.

In certain embodiments, the organic solvent is an aromatic hydrocarbonor a mixture containing thereof. In one embodiment, the aromatichydrocarbon contains 7 to 12 carbon atoms.

In certain embodiments, the organic solvent is a straight-chain C₁₁ toC₂₀ hydrocarbon or a mixture containing thereof.

In certain embodiments, the organic solvent is an ether or a mixturecontaining thereof. In one embodiment, the ether is diphenyl ether,diethylene glycol dimethyl ether, or diethylene glycol dibutyl ether. Inone embodiment, the organic solvent is a mixture of diphenyl ether withxylene and/or ethyl acetate.

In certain embodiments, the mass ratio of the phenolic compound and theorganic solvent is no less than 1:1. In one embodiment, the mass ratioof the phenolic compound and the organic solvent is no less than 1.25:1.

In certain embodiments, the phenolic compound is phenol, an alkylphenol, or an arylalkyl phenol. In one embodiment, the phenolic compoundis a para-tert-C₄-C₈ alkyl phenol. In one embodiment, the phenoliccompound is benzyl phenol or cumyl phenol.

In certain embodiments, the aldehyde is formaldehyde orparaformaldehyde.

Embodiments of the invention also include a phenolic oligomercomposition prepared by the process described in this aspect of theinvention and any of the above embodiments of this aspect of theinvention.

Another aspect of the invention relates to a process for the selectivesynthesis of a calix[8]arene compound. The process comprises reacting aphenolic compound, an aldehyde, and a nitrogen-containing base as acatalyst, in the presence of an organic solvent. The process furthercomprises heating the reaction mixture at an elevated temperature ofabout 140° C. to about 180° C. for a time period of 4 hours or longer,to remove water from the reaction mixture and selectively produce acalixarene compound containing at least 70% calix[8]arene.

In certain embodiments, the heating step at the water removal stage iscarried out over a time period of 6 hours or longer to selectivelyproduce a calixarene compound containing at least 90% calix[8]arene. Inone embodiment, the heating step at the water removal stage is carriedout over a time period of 6 hours or longer to selectively produce acalixarene compound containing at least 92% calix[8]arene.

In certain embodiments, the elevated temperature at the water removalstage ranges from about 140° C. to about 150° C.

In certain embodiments, the reacting step is carried out under refluxconditions. In certain other embodiments, the aldehyde isparaformaldehyde and the reaction is carried out without reflux.

In certain embodiments, the phenolic compound is phenol, an alkylphenol, or an arylalkyl phenol. In one embodiment, the phenolic compoundis a para-tert-C₄-C₈ alkyl phenol. In one embodiment, the phenoliccompound is benzyl phenol or cumyl phenol.

In certain embodiments, the aldehyde is formaldehyde orparaformaldehyde.

Embodiments of the invention also include a phenolic oligomercomposition prepared by the process described in this aspect of theinvention and in any of the above embodiments of this aspect of theinvention.

Yet another aspect of the invention relates to a process for a one-step,selective synthesis of a high-purity calix[8]arene compound. The processcomprises reacting, in a one-step process, a phenolic compound and analdehyde in the presence of a base catalyst to form a high-puritycalix[8]arene compound, without carrying out a recrystallization step.

In certain embodiments, the process further comprises filtrating thereaction product and drying the filtrated reaction product, therebyproducing a calix[8]arene compound with a purity of about 95% or higher.In one embodiment, the process further comprises filtrating the reactionproduct and drying the filtrated reaction product, thereby producing acalix[8]arene compound with a purity of about 98% or higher.

In certain embodiments, the phenolic compound is phenol, an alkylphenol, or an arylalkyl phenol. In one embodiment, the phenolic compoundis a para-tert-C₄-C₈ alkyl phenol. In one embodiment, the phenoliccompound is benzyl phenol or cumyl phenol.

In certain embodiments, the aldehyde is formaldehyde orparaformaldehyde.

Embodiments of the invention also include a phenolic oligomercomposition prepared by the process described in this aspect of theinvention and in any of the above embodiments of this aspect of theinvention.

Another aspect of the invention relates to a process for the selectivesynthesis of a calix[8]arene compound with a low free phenolic monomercontent. The process comprises the steps of reacting a phenolic compoundand an aldehyde in the presence of a base catalyst, and washing thereaction product to remove free phenolic compound monomers, to produce acalix[8]arene compound with a free phenolic monomer content of about0.5% or lower. The process does not include a recrystallization step.

In certain embodiments, the free phenolic monomer content is about 0.1%or lower.

In certain embodiments, the process further comprises filtrating thewashed reaction product and drying the filtrated reaction product,thereby producing a high-purity calix[8]arene compound with a purity ofabout 95% or higher.

In certain embodiments, the phenolic compound is phenol, an alkylphenol, or an arylalkyl phenol. In one embodiment, the phenolic compoundis a para-tert-C₄-C₈ alkyl phenol. In one embodiment, the phenoliccompound is benzyl phenol or cumyl phenol.

In certain embodiments, the aldehyde is formaldehyde orparaformaldehyde.

Embodiments of the invention also include a phenolic oligomercomposition prepared by the process described in this aspect of theinvention and in any of the above embodiments of this aspect of theinvention.

Another aspect of the invention relates to a calixarene compoundcomprising n units of formula (A-1):

In formula (A-1), each of R₁ and R₂ is independently linear, branched,or cyclic C₁-C₃₀ alkyl, aryl, alkylaryl, or arylalkyl. Each L isindependently selected from the group consisting of —CH₂—, —C(O)—,—CH(R₃)—, —(CH₂)_(n′)—O—(CH₂)_(n′)—, —C(R₃)₂—. Each R₃ is independentlya C₁-C₆ alkyl. Integer n ranges from 2-20. Each n′ is independently aninteger from 1-2. Each A₁ represents a direct covalent bond to anadjacent unit of formula (A-1) such that there is one L group betweenadjacent units, whereby the total units in the calixarene compound forma ring. In one embodiment, each of R₁ and R₂ is independently linearC₁-C₆ alkyl. For instance, each R₁ is methyl, and each R₂ is methyl,ethyl, propyl, or hexyl. In one embodiment, the integer n is 8. In oneembodiment, the calixarene compound has the structure of

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the GPC results of the final reaction mass prepared fromExample 1.

FIG. 2 shows the ¹H-NMR results of the final reaction mass prepared fromExample 1.

FIG. 3 shows the GPC results of the crude reaction mass prepared fromExample 2.

FIG. 4 shows the ¹H-NMR results of the crude reaction mass prepared fromExample 2.

FIG. 5 shows the GPC results of the crude reaction mass prepared fromExample 3.

FIG. 6 shows the ¹H-NMR results of the crude reaction mass prepared fromExample 3.

FIG. 7 shows the GPC results of the crude reaction mass prepared fromExample 4.

FIG. 8 shows the ¹H-NMR results of the crude reaction mass prepared fromExample 4.

FIG. 9 shows the GPC results of the crude reaction mass prepared fromExample 5.

FIG. 10 shows the ¹H-NMR results of the crude reaction mass preparedfrom Example 5.

FIG. 11 shows the GPC results of the crude reaction mass prepared fromExample 6.

FIG. 12 shows the ¹H-NMR results of the crude reaction mass preparedfrom Example 6.

FIG. 13 shows the GPC results of the final reaction mass taken from thefinal sample (tF) prepared from Example 7.

FIG. 14A shows the ¹H-NMR results of the reaction mass taken from samplet0 prepared from Example 7. FIG. 14B shows the ¹H-NMR results of thereaction mass taken from sample t4 prepared from Example 7. FIG. 14Cshows the ¹H-NMR results of the final reaction mass taken from the finalsample (tF) prepared from Example 7.

FIG. 15 shows the plot of % tert-butylcalix[8]arene of total reactionproducts and the reactor temperature against the time of the waterremoval, during the distillation stage in Example 7.

FIG. 16A shows the ¹H-NMR results of the cyclic components of the finalreaction mass after column chromatography (sample tC), prepared fromExample 7. FIG. 16B shows the TGA results of the cyclic components ofthe final reaction mass after column chromatography (sample tC),prepared from Example 7. FIG. 16C shows the HPLC results of the cycliccomponents of the final reaction mass after column chromatography(sample tC), prepared from Example 7. FIG. 16D shows the HPLC results ofa commercially available tert-butylcalix[8]arene sample.

FIG. 17A shows the ¹H-NMR results of the sample taken from the reactionmass after one hour of reaching reflux, prepared from Example 8. FIG.17B shows the ¹H-NMR results of the sample taken from the reaction massafter seven hours of reaching reflux, prepared from Example 8. FIG. 17Cshows the ¹H-NMR results of the sample taken from the reaction massafter twelve hours of reaching reflux, prepared from Example 8. FIG. 17Dshows the ¹H-NMR results of the sample taken from the final reactionmass after the end of reflux and distillation (final), prepared fromExample 8.

FIG. 18A shows the low-set GPC results of the sample taken from thereaction mass after one hour of reaching reflux, prepared from Example8. FIG. 18B shows the low-set GPC results of the sample taken from thereaction mass after twelve hours of reaching reflux, prepared fromExample 8.

FIG. 19 is a graph showing the reaction kinetics of the reaction betweenPTBP, 100 mol % HCHO, and TEAOH, determined by means of low-set GPC,¹H-NMR, and wt % of PTBP and HCHO.

FIG. 20 shows the GPC results of the crude reaction mass prepared fromExample 9.

FIG. 21 shows the ¹H-NMR results of the crude reaction mass preparedfrom Example 9.

FIG. 22 shows the GPC results of the crude reaction mass prepared fromExample 11.

FIG. 23 shows the ¹H-NMR results of the crude reaction mass preparedfrom Example 11.

FIG. 24 shows the GPC results of the crude reaction mass prepared fromExample 12.

FIG. 25 shows the ¹H-NMR results of the crude reaction mass preparedfrom Example 12.

FIG. 26 shows the GPC results of the crude reaction mass prepared fromExample 13.

FIG. 27 shows the GPC results of the crude reaction mass prepared fromExample 14.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the invention relates to a process for preparing acalixarene compound, comprising reacting a phenolic compound and analdehyde in the presence of at least one nitrogen-containing base as acatalyst to form a calixarene compound.

The phenolic compound may be a monohydric, dihydric, or polyhydricphenol, or its derivative, with or without substituent(s) on the benzenering of the phenolic compound. Suitable monohydric, dihydric, orpolyhydric phenols include, but are not limited to, phenol;dihydric-phenols such as resorcinol, catechol, and hydroquinone;trihydric-phenols such as pyrogallol, hydroxy quinol, or phloroglucinol;dihydroxybiphenol such as 4,4′-biphenol; alkylidenebisphenols (thealkylidene group can have 1-12 carbon atoms) such as4,4′-methylenediphenol (bisphenol F), and 4,4′-isopropylidenediphenol(bisphenol A); trihydroxybiphenol; and thiobisphenols. Exemplarymonohydric, dihydric, or polyhydric phenols include phenol, resorcinol,and pyrogallol. In one embodiment, the phenolic compound is phenol.

Suitable phenolic compounds also include a monoether derivative ordiether derivative of the monohydric, dihydric, or polyhydric phenols.The ether derivative of the monohydric, dihydric, or polyhydric phenolsmay be an alkyl ether, an aryl ether, or an alkyl aryl ether, which maybe optionally substituted with a hydroxy, alkoxy, alkylene oxide, oracryloxy group. For instance, the ether derivative may be a monoalkylether, dialkyl ether, monoglycidyl ether, diglycidyl ether, or benzyloxyether group, or mixtures thereof.

The benzene ring of the monohydric, dihydric, or polyhydric phenol, orits derivative can be substituted in the ortho, meta, and/or parapositions by one or more linear, branched, or cyclic C₁-C₃₀ alkyl, orhalogen (F, Cl, or Br). The one or more substituents on the benzene ringof the phenolic compound may be C₁-C₃₀ alkyl, aryl, alkylaryl, orarylalkyl. For example, the benzene ring of the phenolic compound can besubstituted by C₁-C₂₄ alkyl, C₁-C₁₆ alkyl, C₄-C₁₆ alkyl, or C₄-C₁₂ alkyl(such as tert-C₄-C₁₂ alkyl). Suitable substituents on the benzene ringalso include aryl, such as phenyl; C₁-C₃₀ arylalkyl (such as benzyl orcumyl); or C₁-C₃₀ alkylaryl.

In certain embodiments, the phenolic compound is phenol, resorcinol,pyrogallol, 4,4′-biphenol, 4,4′-methylenediphenol, or4,4′-isopropylidenediphenol, each having the benzene ring beingsubstituted with H or C₁-C₂₄ alkyl (e.g., C₄ to C₁₂ alkyl).

In certain embodiments, the phenolic compound is a mono- or di-ether(e.g., a C₁-C₆ alkyl ether or glycidyl ether) of phenol, resorcinol,pyrogallol, 4,4′-biphenol, 4,4′-methylenediphenol, or4,4′-isopropylidenediphenol, each having the benzene ring beingsubstituted with H or C₁-C₂₄ alkyl (e.g., C₄ to C₁₂ alkyl).

When the phenolic compound is a substituted phenol, the phenoliccompound typically contains one substituent at the para position. In oneembodiment, the phenolic compound is phenol, an arylalkyl phenol (suchas para-benzylphenol or para-cumylphenol), or an alkylphenol,particularly a para-C₁-C₂₄ (linear, branched, or cyclic) alkylphenol,such as para-methylphenol, para-ethylphenol, para-isopropylphenol,para-tert-butylphenol (PTBP), para-sec-butylphenol, para-tert-amylphenol(PTAP), para-tert-hexylphenol, para-cyclohexylphenol,para-sec-octylphenol, para-tert-octylphenol (PTOP), para-isooctylphenol,para-decylphenol, para-dodecylphenol, para-tetradecyl phenol,para-octadecylphenol, para-nonylphenol, para-pentadecylphenol,para-cetylphenol, para-adamantylphenol, andpara-(2-isopropyl-5-methylcyclohexyl)phenol. Typical alkyl phenolsinclude para-tert-C₄-C₁₂ alkylphenols, such as para-tert-C₄-C₈alkylphenols.

Suitable phenolic compounds also include those phenols described inGutsche, “Chapter 1. Synthesis of Calixarenes and thiacalixarenes,”Calixarenes 2001 (Edited by M.-Z. Asfari et. al., Kluwer AcademicPublishers, 2001), pages 1-25, which is incorporated herein by referencein its entirety, to the extent not inconsistent with the subject matterof this disclosure.

In certain embodiments, the process is used for preparing a calixarenecompound with a high solid-content, or for the selective synthesis of acalix[8]arene compound. Exemplary phenolic compounds are phenol, a C₄ toC₈ alkyl phenol (linear, branched, or cyclic) (e.g., a para-tert-C₄-C₈alkylphenol), and an arylalkyl phenol (such as benzyl phenol or cumylphenol).

Any aldehyde known in the art for preparing a phenolic resin (linear orcyclic) is suitable in this process. Exemplary aldehydes includeformaldehyde, methyl formcel (i.e., formaldehyde in methanol), butylformcel, acetaldehyde, propionaldehyde, butyraldehyde, crotonaldehyde,valeraldehyde, caproaldehyde, heptaldehyde, benzaldehyde, as well ascompounds that decompose to aldehyde such as paraformaldehyde, trioxane,furfural (e.g., furfural or hydroxymethylfurfural),hexamethylenetriamine, aldol, 3-hydroxybutyraldehyde, and acetals, andmixtures thereof. A typical aldehyde used is formaldehyde orparaformaldehyde.

To prepare a calixarene compound, the molar ratio of the total amount ofthe phenolic compounds to the total amount of the aldehyde added to thereaction typically ranges from about 0.5:1 to about 2:1, for instance,from about 1:1.5 to about 1.5:1, from about 1:1.3 to about 1.3:1, orfrom about 1:1.15 to about 1:1.

The term “calixarene” generally refers to a variety of derivatives thatmay have one or more substituent groups on the hydrocarbons ofcyclo{oligo[(1,3-phenylene)methylene]}. The term “calixarene” alsogenerally encompasses the cyclic structure formed by not only amonohydric phenol, such as phenol or alkylphenol, but also a dihydric orpolyhydric phenol, or a derivative thereof. The calixarenes may containa substituent on the benzene ring of calixarenes. Exemplary cyclicstructures of the calixarenes are those formed by phenol, resorcinol, orpyrogallol.

A typical calixarene compound based on phenols has a structure ofFormula (A′):

A typical calixarene compound based on resorcinols has a structure ofFormula (B-1′) or (B-2′):

A typical calixarene compound based on pyrogallols has a structure ofFormula (C′):

In Formulas (A′), (B-1′), (B-2′), and (C′), the substituent group R₁ onthe benzene ring of the calixarene compound depends on the phenoliccompounds used in the process to prepare the calixarene compound. Forinstance, R₁ may be H, C₁-C₃₀ alkyl, aryl, alkylaryl, or arylalkyl. Allabove descriptions in the context of the substituents on the benzenering of the phenolic compound are applicable to the definition of R₁.The number of units of phenolic monomers of the calixarene (e.g., n inFormulas (A′), (B-1′), (B-2′), and (C′)) may be 2 to 100, for instance,2 to 50, 2 to 30, 2 to 20, 2 to 10, 2 to 8, 2 to 6, or 2 to 4, resultingin a molecular weight typically ranging from about 500 to about 25,000daltons, from about 500 to about 10,000 daltons, from about 500 to about5,000 daltons, from about 1,000 to about 5,000 daltons, from about 500to about 3,000 daltons, or from about 500 to about 1,000 daltons.

In certain embodiments, the calixarene compound comprises n units ofphenolic monomers of Formula (A):

in which the substituent group R on the benzene ring of the calixarenecompound depends on the phenolic compounds used in the process toprepare the calixarene compound. For instance, R may be H, C₁-C₃₀ alkyl,aryl, alkylaryl, or arylalkyl. All above descriptions in the context ofthe substituents on the benzene ring of the phenolic compound areapplicable to the definition of R. Each A₁ represents a direct covalentbond to an adjacent unit of Formula (A) such that there is one L groupbetween adjacent units, whereby the total units in the calixarenecompound form a ring. The L group depends on the aldehyde used in theprocess to prepare the calixarene compound. For instance, each L may beindependently selected from the group consisting of —CH₂—, —C(O)—,—CH(R₃)—, —(CH₂)_(n′)—O—(CH₂)_(n′)—, and —C(R₃)₂—; each R₃ may beindependently a C₁-C₆ alkyl; and each n′ may be independently an integerfrom 1 to 2. Typically, when formaldehyde is used, L may be —CH₂— or—CH₂—O—CH₂—.

Typically, in the case of a monohydric phenol with a substituent groupbeing used to form the calixarene compound, if the substituent group isat the para position to the hydroxyl group of the phenolic compound, theresulting alkylene bridge (e.g., methylene bridge if formaldehyde isused) extends in the ortho positions to the hydroxyl group of thephenolic compound (see, e.g., Formula (A′)). If the substituent group isat the ortho position to the hydroxyl group of the phenolic compound,the resulting alkylene bridge can extend in the para position to thehydroxyl group of the phenolic compound and the other substituted orthoposition to the hydroxyl group of the phenolic compound. In the case ofa dihydric phenol being used to form the phenolic resin, the location ofthe alkylene bridge (e.g., methylene bridge if formaldehyde is used) canalso vary depending on the relative position of the hydroxyl groups andthe substituent groups. For instance, two possible connections of thephenolic units are shown in Formula (B-1′) and (B-2′) above. In the caseof a trihydric phenol being used to form the phenolic resin, thelocation of the alkylene bridge (e.g., methylene bridge if formaldehydeis used) can also vary depending on the relative positions of thehydroxyl groups and the substituent group. For instance, a possibleconnection of the phenolic units is shown in Formula (C′) above.

The number of units of phenolic monomers in the calixarene compound(e.g., n in the context of Formula (A)) may be 2 to 100, for instance, 2to 50, 2 to 30, 2 to 20, 2 to 10, 2 to 8, 2 to 6, or 2 to 4, resultingin a molecular weight typically ranging from about 500 to about 25,000daltons, from about 500 to about 10,000 daltons, from about 500 to about5,000 daltons, from about 1,000 to about 5,000 daltons, from about 500to about 3,000 daltons, or from about 500 to about 1,000 daltons.

The term “calix[n]arene” typically specifies the number of units ofphenolic monomers in the calixarene compound prepared. For instance, acalix[8]arene compound is a calixarene compound having 8 units ofphenolic monomers.

An exemplary calix[8]arene structure is shown as below:

in which the phenolic compound used in the process has a substituentgroup, R, at the para position to the hydroxyl group of the phenoliccompound and the aldehyde used in the process is formaldehyde.

The calixarene compound may be prepared from one or more phenoliccompounds reacting with one or more aldehydes forming an oligomer ofphenolic monomers. The resulting calixarene compound may be ahomopolymer of the same phenolic monomer, or a copolymer containingdifferent units of phenolic monomers, e.g., when two or more differentphenolic compounds were reacted with an aldehyde.

In certain embodiments, the phenolic units in the calixarene compoundcan be resulting from the same or different phenolic compounds. Thebenzene ring of each phenolic unit can be independently substituted witha same or different substituent group R. For instance, the phenolicunits in the calixarene compound are the same or different phenols, andthe benzene ring of each phenol is independently substituted with H orC₁ to C₂₀ alkyl (e.g., C₄ to C₁₂ alkyl).

In certain embodiments, the calixarene compound comprises n units ofphenolic monomers of Formula (A-1):

in which each of R₁ and R₂ is independently linear, branched, or cyclicC₁-C₃₀ alkyl, aryl, alkylaryl, or arylalkyl. For instance, each of R₁and R₂ may be independently C₁-C₁₂ alkyl (linear, branched, or cyclic),or C₁-C₆ alkyl (linear). In one embodiment, each R₁ is methyl, and eachR₂ is methyl, ethyl, propyl, or hexyl.

Each A₁ represents a direct covalent bond to an adjacent unit of Formula(A-1) such that there is one L group between adjacent units, whereby thetotal units in the calixarene compound form a ring. The L group dependson the aldehyde used in the process to prepare the calixarene compound.For instance, each L may be independently selected from the groupconsisting of —CH₂—, —C(O)—, —CH(R₃)—, —(CH₂)_(n′)—O—(CH₂)_(n′)—, and—C(R₃)₂—; each R₃ may be independently a C₁-C₆ alkyl; and each n′ may beindependently an integer from 1 to 2. Typically, when formaldehyde isused, L is —CH₂— or —CH₂—O—CH₂—.

The total number of units in the calixarene compound of Formula (A-1),i.e., n, is an integer that typically ranges from 2-20. In oneembodiment, n is from 4-10, for instance, 4, 5, 6, 7, 8, 9, or 10.

In one embodiment, the substituent group

on the calixarene compound of Formula (A-1) is at the para position tothe hydroxyl group.

The calixarene compounds described above can exist in one or morestereoisomeric forms, depending on the reaction conditions and/or thechirality of the starting phenolic compounds. For instance, when using aphenolic compound with a chiral center

(* indicates the chiral center), the resulting calixarene compound maycontain stereoisomeric forms, e.g.,

(* indicates the chiral center). However, the calixarene compounds maybe a mixture in which the stereoisomeric forms may not be easy to beseparated. When the starting phenolic compound does not contain a chiralcenter (for instance, an isopropylphenol), the resulting calixarenecompounds would not form different diastereomers.

Exemplary calixarene compounds for the calixarene compound of Formula(A-1) have the structures of

Catalyst

A nitrogen-containing base, such as a sterically hindered amine, has aweaker basicity than most alkaline base catalysts, such as sodiumhydroxide or potassium hydroxide, the catalysts conventionally used forthe synthesis of calixarene compounds, including a calix[8]arenecompound. Thus, the conventional alkaline base catalysts convert theformaldehyde faster during the condensation reaction, following akinetic route different than the kinetic route when using anitrogen-containing base, such as a sterically hindered amine, as thecatalyst. Because of this, these conventional alkaline base catalyststypically produce significant amounts of other ring-sized calixarenes(e.g., about 13% of calix[4]arenes and calix[6]arenes). Thenitrogen-containing base catalysts discussed herein, however, allow fora slower build-up of desirable linear precursors for the cycliccompounds (calixarenes) formation, thereby eventually resulting in ahigher selectivity toward calix[8]arenes. Because of their weakerbasicity than conventional alkaline base catalysts, thenitrogen-containing base catalysts discussed herein also display milderreaction conditions.

The nitrogen-containing base used herein typically has a relatively highboiling point. For instance, the nitrogen-containing base may have aboiling point of no less than about 80° C., for instance, no less thanabout 90° C., no less than about 100° C., no less than about 110° C., noless than about 120° C., no less than about 130° C., or no less thanabout 140° C. Because of this high boiling point, thenitrogen-containing base is usually not removed during the reaction ofthe phenolic compounds and the aldehyde, under the reflux and/ordistillation conditions.

In addition, when using the nitrogen-containing base as a catalyst forthe reaction between the phenolic compound and aldehyde, the weak acidphenol can protonate the nitrogen atom in the nitrogen-containing base.This prevents, or substantially inhibits, the nitrogen-containing basefrom being removed during the reaction of the phenolic compounds andaldehyde, under the reflux and/or distillation conditions.

As defined herein, a nitrogen-containing base may generally include asterically hindered amine (e.g., a sterically hindered primary amine, asterically hindered secondary amine, and a sterically hindered tertiaryamine) and a sterically hindered quaternary ammonium hydroxide, such asa tetraalkyl ammonium hydroxide.

Suitable sterically hindered amine compounds include an amidine compoundhaving the formula of

and a guanidine compound having the formula of

For the amidine compounds having the formula of

R₁, R₂, R₃, and R₄ are each independently H, alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; or any two or more of R₁, R₂, R₃,and R₄ can be bonded together to form a five- to nine-membered ringstructure. For instance, R₁, R₂, R₃, and R₄ are each independently H, C₁to C₈ alkyl, C₅ to C₇ cycloalkyl, C₅ to C₇ heterocycloalkyl, phenyl, orC₅ to C₇ heteroaryl; or any two or more of R₁, R₂, R₃, and R₄ can bebonded together to form a five-, six-, or seven-membered ring structure.

Suitable amidine compounds include 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,2-dimethyl-1,4,5,6-tetrahydropyrimidine,1-ethyl-2-methyl-1,4,5,6-tetrahydropyrimidine,1,2-diethyl-1,4,5,6-tetrahydropyrimidine,1-n-propyl-2-methyl-1,4,5,6-tetrahydropyrimidine,1-isopropyl-2-methyl-1,4,5,6-tetrahydropyrimidine,1-ethyl-2-n-propyl-1,4,5,6-tetrahydropyrimidine, and1-ethyl-2-isopropyl-1,4,5,6-tetrahydropyrimidine. Exemplary amidinecompounds used as the catalyst include

For the guanidine compounds having the formula of

R₁′, R₂′, R₃′, R₄′, and R₅′ are each independently H, alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; or any two or more of R₁′, R₂′,R₃′, R₄′, and R₅′ can be bonded together to form a five- tonine-membered ring structure. For instance, R₁′, R₂′, R₃′, R₄′, and R₅′are each independently H, C₁ to C₈ alkyl, C₅ to C₇ cycloalkyl, C₅ to C₇heterocycloalkyl, phenyl, or C₅ to C₇ heteroaryl; or any two or more ofR₁′, R₂′, R₃′, R₄′, and R₅′ can be bonded together to form a five-,six-, or seven-membered ring structure.

Suitable guanidine compounds include 1-methylguanidine,1-n-butylguanidine, 1,1-dimethylguanidine, 1,1-diethylguanidine,1,1,2-trimethylguanidine, 1,2,3-trimethylguanidine,1,3-diphenylguanidine, 1,1,2,3,3-pentamethylguanidine,2-ethyl-1,1,3,3-tetramethylguanidine,1,1,3,3-tetramethyl-2-n-propylguanidine,1,1,3,3-tetramethyl-2-isopropylguanidine,2-n-butyl-1,1,3,3-tetramethylguanidine,2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,2,3-tricyclohexylguanidine,1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD),7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD),7-ethyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-n-propyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-isopropyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-n-butyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-isobutyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-tert-butyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-cyclohexyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-n-octyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-2-ethylhexyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene,7-decyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. Exemplary guanidinecompounds used as the catalyst include

Other suitable nitrogen-containing bases include sterically hinderedprimary amines (e.g., triphenylmethylamine or1,1-diethyl-n-propylamine); sterically hindered secondary amines (e.g.,dicyclohexylamine, t-butylisopropylamine, di-t-butylamine,cyclohexyl-t-butylamine, di-sec-butylamine, dicyclopentylamine,di-(α-trifluoromethylethyl)amine, or di-(α-phenylethyl)amine));sterically hindered tertiary amines (e.g., dicyclohexylmethylamine,ethyldiisopropylamine, dimethylcyclohexylamine, dimethylisopropylamine,methylisopropylbenzylamine, methylcyclopentylbenzylamine,isopropyl-sec-butyl-trifluoroethylamine, diethyl-(α-phenylethyl)amine,trialkylenediamine such as triethylenediamine(1,4-diazabicyclo[2.2.2]octane, DABCO), or trialkylamine such astrimethylamine, triethylamine or tri-n-propylamine); morpholinecompounds (e.g., morpholine, N-ethylmorpholine, N-methylmorpholine,dimorpholinodimethylether, or dimorpholinodiethylether); imidazolecompounds (e.g., imidazole, 2-methylimidazole, n-methylimidazole, or1,2-dimethylimidazole); pyridine compounds (e.g., pyridine,4-methylaminopyridine, 2-methylaminopyridine, or4-dimethylaminopyridine); triamine compounds (e.g.,N,N,N′,N′,N″,N″-pentamethyldiethylenetriamine,N,N,N′,N′,N″,N″-pentaethyldiethylenetriamine, orN,N,N′,N′,N″,N″-pentamethyldipropylenetriamine), and amino-containingether compounds (e.g., bis(dimethylaminoethyl)ether,bis(diethylaminoethyl)ether, or bis(dimethylaminopropyl)ether).Exemplary nitrogen-containing bases from this group includetriethylamine

ethyldiisopropylamine

imidazole

2-methylimidazole

pyridine, and 4-dimethylaminopyridine

The sterically hindered quaternary ammonium hydroxide typically includesa tetraalkyl ammonium hydroxide. Each alkyl moiety in the tetraalkylammonium hydroxide can be independently C₁ to C₆ alkyl, for instance, C₁to C₄ alkyl. Exemplary tetraalkyl ammonium hydroxides used as thecatalyst include tetramethyl ammonium hydroxide

tetraethylammonium hydroxide

tetrapropylammonium hydroxide

and tetrabutylammonium hydroxide

The molar ratio of the total amount of the phenolic compounds to thenitrogen-containing base catalyst added to the reaction typically rangesfrom about 200:1 to about 20:1, for instance, from about 100:1 to about40:1, from about 70:1 to about 40:1, or from about 65:1 to about 45:1.

Solvent

The reaction of the phenolic compound and the aldehyde is typicallycarried out in the presence of an organic solvent. Suitable organicsolvents are non-reactive and have low viscosity, including but notlimited to, aliphatic solvents including alkanes (such as alkanes having4 to 24 carbon atoms; e.g., alkanes having 11 to 20 carbon atoms, orhaving 5 to 16 carbon atoms) and cycloalkanes (such as cycloalkaneshaving 3 to 24 carbon atoms; e.g., cycloalkanes having 5 to 16 carbonatoms); aromatic solvents (such as alkylbenzenes or naphthalenes; e.g.,an aromatic hydrocarbon solvent containing 7 to 12 carbon atoms); ethersincluding aromatic ethers (such as diphenyl ether) and ethers based onethylene glycol (such as diethylene glycol dibutyl ether or diethyleneglycol dimethyl ether); and mixtures containing thereof.

Exemplary organic solvents include xylene, toluene, benzene,naphthalene, an aromatic 150 fluid (i.e., an aromatic hydrocarbonsolvent having a main component ranging from 9 to 12 carbon atoms, suchas Solvesso™ 150 fluid or other similar aromatic hydrocarbon solventsmarketed under different brands), diphenyl ether, diethylene glycoldimethyl ether, diethylene glycol dibutyl ether, Dowtherm® A (a mixtureof diphenylether and biphenyl), nonane, octane, hexadecane, and mixturescontaining thereof.

Suitable organic solvents also include those hydrocarbon solvents havinga high boiling point, such as a straight-chain C₁₁ to C₂₀ hydrocarbonhaving a boiling point ranging from about 250 to about 260° C., andmixtures containing thereof. Such solvents can be obtained from apetroleum middle distillate that contain a paraffin mixture having adistillation range from about 250 to about 260° C. Using high boilingpoint solvents may also result in a higher yield and higher selectivitytoward cyclic compounds (calixarenes) over linear compounds (linearphenolic resins) in the cyclization phase, compared against the organicsolvents with a lower boiling point (such as A-150). In one embodiment,tert-octylcalix[8]arenes prepared in hexadecane has an isolated yield ofabout 15% higher than the isolated yield of tert-octylcalix[8]arenesprepared in A-150, with the reaction reagents/conditions otherwise beingthe same.

It is believed that the polarity of the organic solvents may be used toadjust the kinetics of the reaction, resulting in different linearprecursor formation during the reflux phase or different crystallizationbehavior during the cyclization phase (or distillation phase), therebyadjusting the selectivity of the resulting calixarene compounds. Forinstance, the organic solvents with a higher polarity or nucleophilicity(that is, the ability of the solvent to interact with polar transitionstates in the polycondensation reaction), such as diphenyl ether, maymodify the activity of the nitrogen-containing base catalyst in a way toimprove the formation of the amount of the desired linear precursornecessary to form the desired calixarene compounds. This could result ina higher yield and higher selectivity toward cyclic compounds(calixarenes) over linear compounds (linear phenolic resins) in thecyclization phase, compared against the organic solvents with a lowerpolarity or nucleophilicity (such as xylene or A-150). In oneembodiment, tert-amylcalix[8]arenes prepared in diphenylether/xylenemixture has an isolated yield of about 5% higher than the isolated yieldof tert-amylcalix[8]arenes prepared in A-150, with the reactionreagents/conditions otherwise being the same.

Additionally, when a high boiling point solvent is used, one or moreother organic solvents may be added as an azeo-carrier. For instance,when a high-boiling-point solvent, such as diphenyl ether, is used inthe reaction, this solvent alone does not form azeotropes with water dueto its high boiling point. When water is produced in the reactionsystem, it is actually released above its boiling point of 100° C. and,thus, would enter the vapor phase causing significant foaming. Adding anazeo-carrier can mitigate this boil-over issue by forming azeotropeswith water and constantly removing water from the reaction mass.Exemplary azeo-carrier solvents are xylene and ethyl acetate. Anexemplary organic solvent used in the reaction is a mixture of diphenylether with xylene and/or ethyl acetate.

Typically, the calixarene compounds formed have poor solubility at roomtemperature in a typical hydrocarbon solvent, with some exceptions suchas para-nonylcalixarenes and para-dodecylcalixarenes which may be liquidat room temperature. Conventionally, solid calixarene compounds aresynthesized under high-dilution conditions, meaning that the reaction ofthe phenolic compound and the aldehyde are typically conducted in alarge amount of an organic solvent (e.g., with the solvent concentrationof about 80-85 wt %). A highly diluted system is typically needed forconventional methods to obtain a high amount of solid cyclic compounds(e.g., 17-20% solid contents); otherwise, a significant amount of linearphenolic resins will form.

In the process discussed in this application, however, the reaction canbe carried out in a highly concentrated reaction system, yet stillresult in a significantly improved solid content (i.e., calixarenecompounds) in the reaction products. To carry out the reaction in ahighly concentrated reaction system, the mass ratio of the phenoliccompound to the organic solvent at the starting of the reaction istypically no less than about 0.25:1, for instance, no less than about0.4:1, no less than about 0.5:1, no less than about 1:1, no less than1.25:1, or no less than 1.5:1. Typically, the mass ratio of the phenoliccompound to the organic solvent at the starting of the reaction rangesfrom about 0.5:1 to about 2:1, from about 1:1 to about 2:1, or fromabout 1.25:1 to about 1.8:1.

When the reaction of the phenolic compounds and the aldehyde undergoesreflux and/or distillation stages, as discussed infra, additionalorganic solvent may be added to the reaction mass, for instance, afterthe reflux stage (if the reflux stage is conducted) and/or before thedistillation stage. This is typically carried out when the reaction masscontains a high amount of solid content and is relatively viscous forsubsequent handling (for instance, the subsequent filtration and washingof the reaction product). The organic solvent added at this stage can bethe same as the one initially loaded in the reaction system or adifferent one.

Even in the scenario when additional organic solvent is added to thereaction mass (e.g., after the reflux stage, if the reflux stage isconducted, and/or before the distillation stage), the total amount oforganic solvent in the reaction system during the entire condensationreaction between the phenolic compound and the aldehyde can still berelative small compared to the conventional high-dilution reactioncondition. To carry out the entire reaction in a highly concentratedreaction system, the mass ratio of the phenolic compound to the totalamount of the organic solvent added during the entire reaction(including the reflux stage, if the reflux stage is conducted, anddistillation stage) is typically no less than about 0.25:1, forinstance, no less than about 0.3:1, no less than about 0.4:1, no lessthan about 0.5:1, or no less than about 1:1. Typically, the mass ratioof the phenolic compound to the total amount of the organic solventadded during the entire reaction ranges from about 0.25:1 to about 2:1,or from about 0.3:1 to about 1.5:1.

Reaction Kinetics

To assist the process in forming high yield, high purity, and highselectivity calix[8]arenes, the reaction of the phenolic compounds andthe aldehyde may first undergo a reflux stage. The reaction is typicallycarried out at an elevated temperature. The temperature range at thereflux stage depends on the boiling point of the organic solvents usedin the reaction system and their azeotropes with water/aldehyde. Foralkanes or ethers such as aromatic hydrocarbons or aromatic ethers, thetemperature to reach the reflux stage typically ranges from about 70° C.to about 130° C., for instance, from about 90° C. to about 120° C., orfrom about 95° C. to about 120° C. For instance, when using an aromatic150 fluid (i.e., an aromatic hydrocarbon solvent having a main componentranging from 9 to 12 carbon atoms; A-150) or an aromatic ether (such asdiphenyl ether) as the organic solvent in the reaction system, thetemperature to reach the reflux stage typically ranges from about 95° C.to about 105° C.; when using xylene as the organic solvent in thereaction system, the temperature to reach the reflux stage typicallyranges from about 90° C. to about 120° C.

The control of the timing of the initial reflux stage can help improvethe yield and selectivity toward the calixarene compound. Typically, thereflux stage lasts for a time period of 10 hours or longer, 12 hours orlonger, or 15 hours or longer. In one embodiment, the reaction kineticsof an exemplary calix[8]arene formation indicates that the selectiveformation of the calixarene compound over the linear phenolic resin orother cyclic byproducts in the distillation phase more likely occursfollowing the 10-hour, 12-hour, 15-hour, or longer initial reflux stage.

It is possible to reduce the reaction time at the reflux stage, yetstill produce a composition having a high yield, high purity, and highselectivity toward calix[8]arenes. For instance, when the heating isconducted in a more rigorous manner to heat the reaction vessel at atemperature that is higher than the temperature needed for reaching areflux stage, the reaction time at the reflux stage can be reducedsignificantly. Heating under pressure can achieve the same effect. Forinstance, when using A-150 as the organic solvent in the reactionsystem, the temperature needed to reach the reflux stage typicallyranges from about 95° C. to about 105° C. However, when the heating isconducted in a more rigorous manner to raise the temperature of thereaction vessel to about 115° C., the reaction time at the reflux stagecan be reduced from 10 hours to 5 hours. In one embodiment, a rigorousheating results in the temperature of the reaction vessel about 5 to 20°C. higher or about 10 to 15° C. higher than the temperature needed forreaching a reflux stage. This higher temperature increases the reactionrate and can reduce the reaction time at the reflux stage to about 80%,about 70%, about 60%, about 50%, about 40%, about 30%, or about 25% ofthe reaction time typically needed for the reflux stage. Accordingly,the reflux time can be reduced to about 4 hours, about 5 hours, about 6hours, about 7 hours, or about 8 hours.

It is not necessary for the reaction to undergo a reflux stage. Forinstance, when paraformaldehyde is used in the reaction, the reactionmay not undergo a reflux stage. This provides the benefit of asignificantly shortened total reaction time, while still affording ahigh yield, high purity, and high selectivity toward calix[8]arenes.

The reaction may also undergo a distillation stage. If a reflux stage isconducted, the distillation stage is typically after the reflux stage.The reaction mixture may be heated at an elevated temperature of 140° C.to 180° C., for instance, from about 140° C. to about 160° C., or fromabout 140° C. to about 150° C., to remove water from the reactionmixture.

The longer the distillation stage, generally the higher the selectivitytoward the calix[8]arene compound. Typically, the distillation stagelasts for a time period of 4 hours or longer, 5 hours or longer, 6 hoursor longer, 7 hours or longer, 8 hours or longer, 9 hours or longer, or10 hours or longer. In one embodiment, the reaction kinetics of anexemplary calix[8]arene formation indicates the increase of theselectivity toward calix[8]arene over calix[6]arene after 3-6 hours ofdistillation.

Purification

The process to produce a calix[8]arene compound with a high yield, highpurity, and high selectivity can be carried out in a one-step reaction,and in a more efficient process, without utilizing a recrystallizationstep.

Instead, a high-purity calix[8]arene compound can be achieved by afiltration step. Accordingly, the process further comprises filtratingthe reaction product directly and drying the filtrated reaction product,thereby producing a calixarene compound containing a high puritycalix[8]arene, for instance, a purity of at least about 90%, at leastabout 92%, at least about 95%, at least about 98%, or at least about99%. The purity of the calix[8]arene compound is characterized by HPLCanalysis, not accounting for the attached solvent and the unreacted freephenolic monomers.

This process can also produce a calixarene compound with a reducedamount of free phenolic monomers, without utilizing more complicatedpost-synthesis treatments. For instance, simply washing the crudereaction product with an organic solvent can remove most, if not all,free phenolic monomers. The process can also further comprise the stepof filtrating the washed reaction product and drying the filtratedreaction product, thereby producing a calixarene compound with a freephenolic monomer content of about 0.5% or lower, about 0.3% or lower, orabout 0.1% or lower.

Another aspect of the invention relates to a process for a high-yield,high solid-content production of a calixarene compound. The processcomprises reacting a phenolic compound, an aldehyde, and a base catalystin the presence of an organic solvent, in a highly concentrated reactionsystem. The mass ratio of the phenolic compound to the organic solventin the reaction system (the organic solvent added at the starting of thereaction, or the total amount of organic solvent added during the entirecondensation reaction) is no less than about 0.25:1, for instance, noless than about 0.4:1, no less than about 0.5:1, no less than about 1:1,no less than 1.25:1, or no less than 1.5:1. The process produces acalixarene-containing product having at least 30% solids, for instance,at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, or at least 65% solids. The base catalyst used is typically anitrogen-containing base catalyst.

Also applicable to this aspect of the invention are all the descriptionsand all embodiments regarding the phenolic compound, the aldehyde, thenitrogen-containing base catalyst, the organic solvent, and theirrelative amounts; the reaction kinetics (including the reflux stageand/or distillation stage); and the purification discussed above in thefirst aspect of the invention relating to the process for preparing acalixarene compound.

Another aspect of the invention relates to a process for the selectivesynthesis of a calix[8]arene compound. The process comprises reacting aphenolic compound, an aldehyde, and a nitrogen-containing base as acatalyst, in the presence of an organic solvent. Optionally, thereacting step is carried out under reflux conditions, for a time periodof 10 hours or longer, 12 hours or longer, or 15 hours or longer, at anormal reflux temperature range, or for a reduced reflux time if heatingis conducted in a more rigorous manner or under pressure, as discussedabove in the first aspect of the invention relating to the process forpreparing a calixarene compound. When paraformaldehyde is used in thereaction, the reaction may not undergo a reflux stage. The processfurther comprises heating the reaction mixture at an elevatedtemperature of about 140° C. to about 180° C. for a time period of 4hours or longer, for instance, 5 hours or longer, 6 hours or longer, 7hours or longer, 8 hours or longer, 9 hours or longer, or 10 hours orlonger, to remove water from the reaction mixture and selectivelyproduce a calixarene compound containing at least 70% calix[8]arene, forinstance, at least about 90%, at least about 92%, at least about 95%, atleast about 98%, or at least about 99% of calix[8]arene.

Also applicable to this aspect of the invention are all the descriptionsand all embodiments regarding the phenolic compound, the aldehyde, thenitrogen-containing base catalyst, the organic solvent, and theirrelative amounts; the reaction kinetics (including the reflux stageand/or distillation stage); and the purification discussed above in thefirst aspect of the invention relating to the process for preparing acalixarene compound.

Another aspect of the invention relates to a process for a one-step,selective synthesis of a high-purity calix[8]arene compound. The processcomprises reacting, in a one-step process, a phenolic compound and analdehyde in the presence of a base catalyst to form a high-puritycalix[8]arene compound, without carrying out a recrystallization step.The base catalyst used is typically a nitrogen-containing base catalyst.

The process can further comprise the step of filtrating the reactionproduct and drying the filtrated reaction product, thereby producing acalix[8]arene compound with a purity of at least about 90%, at leastabout 92%, at least about 95%, at least about 98%, or at least about99%.

Also applicable to this aspect of the invention are all the descriptionsand all embodiments regarding the phenolic compound, the aldehyde, thenitrogen-containing base catalyst, the organic solvent, and theirrelative amounts; the reaction kinetics (including the reflux stageand/or distillation stage); and the purification discussed above in thefirst aspect of the invention relating to the process for preparing acalixarene compound.

Another aspect of the invention relates to a process for the selectivesynthesis of a calix[8]arene compound with a low free phenolic monomercontent. The process comprises the steps of reacting a phenolic compoundand an aldehyde in the presence of a base catalyst, and washing thereaction product to remove free phenolic compound monomers, to produce acalix[8]arene compound with a free phenolic monomer content of about0.5% or lower, for instance, about 0.3% or lower, or about 0.1% orlower. The process does not include a recrystallization step. The basecatalyst used is typically a nitrogen-containing base catalyst.

Also applicable to this aspect of the invention are all the descriptionsand all embodiments regarding the phenolic compound, the aldehyde, thenitrogen-containing base catalyst, the organic solvent, and theirrelative amounts; the reaction kinetics (including the reflux stageand/or distillation stage); and the purification discussed above in thefirst aspect of the invention relating to the process for preparing acalixarene compound.

Other aspects of the invention also relate to a phenolic oligomercomposition prepared by any one of the processes discussed above.

Applications

The calixarene compounds or phenolic oligomer compositions prepared bythe processes disclosed herein can be used in a wide range ofapplications.

One aspect of the invention relates to a demulsifier or dehazercomposition comprising the calixarene compounds or phenolic oligomercompositions prepared by the processes discussed above. The demulsifieror dehazer composition may further comprise one or more other componentscommonly used in a demulsifier or dehazer composition, as understood bythose of skill in the art. The demulsifier or dehazer composition may beused for a wide variety of applications for oil and water separation,such as refinery and fuel dehazing. The demulsifier or dehazercomposition may further act as salt-sequestering agents in crude oil,for instance, to sequester salt from crude oil and as a result, reducesalt levels in crude oil.

The calixarene compounds or phenolic oligomer compositions prepared bythe processes disclosed herein may also be used as the starting materialfor overbasing. For instance, calixarene compounds or phenolic oligomercompositions or their functional derivatives can be attached with metalbase moieties forming an overbased metal salt, to neutralize the acidicmaterials and disperse sludge in lubricating oil compositions or fuelcompositions. See, e.g., salicyclic calixarenes and their use aslubricant additives, described in U.S. Pat. No. 6,200,936, which isincorporated herein by reference in its entirety, to the extent notinconsistent with the subject matter of this disclosure. As anotherexample, an additive package based on overbased calixarene compounds orphenolic oligomer compositions prepared by the processes disclosedherein, e.g., a p-didecylcalixarene compound (such asp-dodecylcalix[5,6,8] compounds), can perform well in the TEOST HMT test(Thermo-Oxidation Engine Oil Simulation Test), which is employed toevaluate the ability of an engine oil to control the formation ofdeposits at high temperatures. See, e.g., salicyclic calixarenes andtheir use as lubricant additives, described in a doctoral thesis byAlessandro Burlini, entitled “SYNTHESIS OF NEW CALIXARENE-BASEDLUBRICANT ADDITIVES,” published by University of Parma, Department ofChemistry (Italy) on Mar. 18, 2016, which is incorporated herein byreference in its entirety, to the extent not inconsistent with thesubject matter of this disclosure.

Another aspect of the invention relates to a paraffin-containing fluidcomposition comprising a resin containing the calixarene compounds orphenolic oligomer compositions prepared by the processes discussedabove, and one or more paraffin-containing fluids. The resin is at leastpartially soluble in the paraffin-containing fluid, and disperses theparaffin in the fluid composition and/or inhibits the deposition of theparaffin crystals. The fluid can be any hydrocarbon fluid in theoilfield including, but not limited to, a crude oil, home heating oil,lubricating oil (such as an engine oil), and natural gas. These oilfieldhydrocarbon fluids typically contain paraffin or paraffin wax. Thecomposition containing the calixarene compounds or phenolic oligomercompositions prepared by the processes may be used for a wide variety ofapplications to disperse paraffin crystals and/or inhibit paraffincrystal deposition, such as for treating a well or vessel surface toreduce the deposition of paraffin crystals on the well or vesselsurface. Additional details on the methods of using calixarene compoundsin inhibiting paraffin crystal deposition may be found in U.S. patentapplication Ser. No. 15/879,293 to Cable et al, entitled “Paraffininhibition by solubilized calixarenes,” filed on Jan. 24, 2018, which isincorporated herein by reference in its entirety, to the extent notinconsistent with the subject matter of this disclosure.

The calixarene compounds or phenolic oligomer composition prepared bythe processes disclosed herein may be used as various other agents orintermediates to prepare other useful agents.

For instance, the calixarene compounds or phenolic oligomer compositionsprepared by the processes disclosed here may be used as charge controlagents to create a desired charge level and polarity, which may beuseful as coating additives that can be applied to surfaces (e.g.,aluminum oil cans), as chemical sensors for determining onset of rustingin applications such as marine coatings or aerospace applications, or intoners for developing electrostatic images used for electrophotography,electrostatic recording, electrostatic printing, etc.

The calixarene compounds or phenolic oligomer composition prepared bythe processes disclosed here may be used as host molecules, to form acomplex or an association with one or more guest molecules, such asions, metals, organic compounds of various sizes, compounds carryingcharges, and salts. By doing so, they may aid in compound delivery(e.g., drug-delivery vehicles) by encapsulating a compound within thecavity of the calixarene compound, thereby aiding in the solubilizationof the guest molecule. Or they may be used as extractants to extractsmall molecules or metal ions (e.g., via chelation or complexation), oract as ionophores to transport the metal ions across cell membranes.These technologies are further illustrated in U.S. Pat. No. 7,524,469,and U.S. Patent Application Publication No. 2012/0145542; both of whichare hereby incorporated by reference in their entirety, to the extentnot inconsistent with the subject matter of this disclosure.

The calixarene compounds or phenolic oligomer compositions prepared bythe processes disclosed here may be used as adhesion promotors toaccelerate polymerization of monomers in an adhesive composition. Thistechnology is further illustrated in Gutsche, “Calixarenes, AnIntroduction,” page 236 (2^(nd) Edition, RSC Publishing, Cambridge, UK)(2008), which is hereby incorporated by reference in its entirety, tothe extent not inconsistent with the subject matter of this disclosure.

The calixarene compounds or phenolic oligomer composition prepared bythe processes disclosed here may be used in as positive or negativeresists, for pattern formation and etching to form a hyperfinestructure. The resulting resists can be used to fabricate printedcircuit boards, sand carving, microelectronics, and patterning andetching of substrates.

The calixarene compounds or phenolic oligomer composition prepared bythe processes disclosed here may be used as catalysts for a variety ofchemical reactions. For example, because of their unique topology,complexes in which a calixarene ligand coordinates to a transition metalare potentially valuable for olefin polymerization. This technology isfurther illustrated in U.S. Pat. No. 6,984,599, which is herebyincorporated by reference in its entirety, to the extent notinconsistent with the subject matter of this disclosure.

The calixarene compounds or phenolic oligomer composition prepared bythe processes disclosed here may be used as antifoulants that may beapplied to surfaces that normally undergo biofouling (e.g., ship hulls),to inhibit biofouling, or disperse preexisting biofouling.

The calixarene compounds or phenolic oligomer composition prepared bythe processes disclosed here may be used as thermal stabilizers, forinstance, as curing agents, to aid in cross-linking in the curingprocesses of polymers.

Additionally, the calixarene compounds or phenolic oligomer compositionprepared by the processes disclosed here can be used in any otherapplications involving the use of a calixarene compound, such asaccelerators, additives, binding agents, stabilizing agents, flameretardants (in which the calixarene compounds or phenolic oligomercomposition prepared by the processes disclosed here can be a hostcompound in a flame retardant composition; see, e.g., WO 2017/087115,which is incorporated herein by reference in its entirety, to the extentnot inconsistent with the subject matter of this disclosure),adsorbent/absorbant materials, sequestering agents, hardeners,API-transportation, etc.

The calixarene compounds or phenolic oligomer compositions prepared bythe processes disclosed here may be further de-alkylated via sulfonationby sulfuric acid or via nitration by nitric acid, using the methodsdescribed in U.S. Pat. Nos. 5,952,526 and 2,868,844; which areincorporated herein by reference in their entirety. The sulfonated ornitrated calixarenes are typically soluble and may be used for variousapplications as described herein.

The calixarene compounds or phenolic oligomer compositions prepared bythe processes disclosed here may be used as tackifier resins in a rubbercompound for tire applications. For instance, the calixarene compoundsor phenolic oligomer compositions or their functional derivatives may beincorporated into rubber compounds as a phenolic tackifier resin or apart of a phenolic tackifier resin to increase the adhesion strengthbetween a fabric or metal wire with the rubber compound.

The calixarene compounds or phenolic oligomer compositions prepared bythe processes disclosed here may be further treated or reacted withanother polymer component to for form a radial polymer, using themethods described in, e.g., U.S. Patent Application Publication No.2017/0051224, which is incorporated herein by reference in its entirety.The resulting calixarene-based radial polymer can be used as viscosityindex improver additives in lubricant compositions.

Additional aspects, advantages and features of the invention are setforth in this specification, and in part will become apparent to thoseskilled in the art on examination of the following, or may be learned bypractice of the invention. The inventions disclosed in this applicationare not limited to any particular set of or combination of aspects,advantages and features. It is contemplated that various combinations ofthe stated aspects, advantages and features make up the inventionsdisclosed in this application.

EXAMPLES

The following examples are given as particular embodiments of theinvention and to demonstrate the practice and advantages thereof. It isto be understood that the examples are given by way of illustration andare not intended to limit the specification or the claims that follow inany manner.

Example 1. Synthesis of tert-butylcalix[8]arenes Using1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the Catalyst

A 2 L round bottom flask, equipped with an overhead stirrer,thermocouple (having a gas inlet, through which nitrogen stream can beapplied), and condenser, was loaded with 550.2 g para-tert-butylphenol(PTBP) briquettes (3.66 mol) and 370.0 g A-150 (Solvesso™ 150 Fluid). Agentle nitrogen flow was applied on the surface of the hot reaction massand the reactor was heated to about 80° C. within 20 minutes. Mixing wasset to 112 rpm. Five minutes later, when all the PTBP and A-150 formed aclear solution, 8.8 g DBU (98%, 0.058 mol) was added dropwise at atemperature of 80° C., and a slight exotherm was observed. The reactionmixture was heated to 85° C. and 220 g of 50 wt % formaldehyde solution(3.66 mol) was added within 1 hour and 20 minutes, while theformaldehyde solution was heated periodically with a heat gun to preventformaldehyde from solidification.

After the formaldehyde addition, the temperature was increased to 90°C., the nitrogen flow was decreased while the circulating cooling waterflow was increased to combat extra moisture in the condenser, and theconditions were held for 30 minutes. A formaldehyde trap was placedunder the condenser, with the arm to the trap wrapped with aluminumfoil. The reaction mixture was heated to reflux for a total of 15 hours.At the end of the reflux, the reaction mass was about 103° C.

The formaldehyde trap was then exchanged against a Dean-Stark trap whichwas filled with A-150. The condenser was placed on top of the Dean-Starktrap and the heating was resumed to remove the water in the reactionsystem. About 2.5 hours later, the temperature of the reaction massreached 111° C., and additional 55.9 g of A-150 was added to the pot.The water removal was facilitated by a slight nitrogen sweep over thesurface of the reaction mass. The temperature of the reaction massreached 145° C. 70 minutes later, and was held at this temperature foradditional 5 hours. The reaction mass became thicker and thicker. Atotal of 165.2 g distillate was taken out, and the product weighed1028.3 g.

The GPC results of the final reaction mass are shown in FIG. 1. FIG. 1shows that the reaction product had a very lean and sharp peak.Theoretically, the solid content of the crude reaction mass wascalculated to be 57.75 wt % (assuming all water from formaldehydesolution and produced from the reaction were removed; and all excessformaldehyde was removed). The final reaction mass contained 2.2 wt %free PTBP (which corresponds to 22.6 g or 4.1 mol % of unreacted PTBP)and less than 15 ppm free formaldehyde.

The ¹H-NMR results of the final reaction mass are shown in FIG. 2. InFIG. 2, the integrals of the phenolic OH protons for the differentcalixarenes in the ¹H-NMR spectra show the high selectivity for thecalix[8]arene.

The yields of the cyclic phenolic resins were determined by furtheranalysis of the ¹H-NMR results of the crude reaction mass. Although the¹H-NMR does not show the unreacted PTBP, the ratio of the integrals ofthe free phenolic OH signals from the calixarenes (between 8.5 and 11ppm; see e.g., Stewart et al., J. Am. Chem. Soc. 121:4136-46 (1999),which is hereby incorporated by reference in its entirety, to the extentnot inconsistent with the subject matter of this disclosure) to theintegrals of the proton signals from the methylene bridges for linearand cyclic resins (between 3.4 to 4.5 ppm) provided an estimate for theyields of the respective calixarenes. The signals of methylols anddibenzylethers are low since they are the precursors of the calixarenesynthesis—the lower their integral values, the better the conversion.

The analysis results of the ¹H-NMR in FIG. 2 are as follows.

Integrals for calixarene phenolic OH protons (for 0.121 all calixarenes)Integrals for two protons of all methylene bridges 0.295 (cyclic andlinear resins) Integrals for one proton of all methylene bridges 0.1475(cyclic and linear resins) Ratio of calixarene phenolic OH protons tothe 0.121/0.1475 = 82.0% protons of all methylene bridgesTaking into account the 4.1 mol % unreacted PTBP in the yieldcalculation (i.e., 95.9 mol % of the PTBP had reacted) resulted in acrude calixarene yield of 78.7% (i.e., 82.0%×0.959). That is to say, thetheoretical yield of all cyclic components in this crude reaction masswas 78.7%.

Applying the same calculation for the tert-butylcalix[8]arene providedthe following results.

Integrals for tert-butylcalix[8]arene phenolic 0.115 OH protonsIntegrals for one proton of all methylene bridges 0.1475 (cyclic andlinear resins) Ratio of tert-butylcalix[8]arene phenolic OH 0.115/0.1475= 78.0% protons to the protons of all methylene bridgesTaking into account the 4.1 mol % unreacted PTBP in the yieldcalculation resulted in a crude tert-butylcalix[8]arene yield of 74.8%(i.e., 78.0%×0.959). That is to say, the theoretical yield oftert-butylcalix[8]arene in this crude reaction mass was 74.8%.

Example 2. Synthesis of tert-butylcalix[8]arenes UsingTetraethylammonium Hydroxide (TEAOH) as the Catalyst (in a More DilutedSystem)

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, overhead addition tank, moisture trap, and condenser wasloaded with 112.7 g PTBP briquettes (0.75 mol) and 100.2 g A-150(Solvesso™ 150 Fluid). A gentle nitrogen flow was applied on the surfaceof the hot reaction mass and the reactor was heated to about 90° C. Whenall the PTBP and A-150 formed a clear solution, 5.5 g TEAOH solution (40wt % in water, 0.015 mol) was added dropwise at a temperature of 87° C.,and this temperature was held for 20 minute. Starting at 87° C., a totalof 43.6 g of 51.7 wt % formaldehyde solution (0.75 mol) was added within12 minutes.

After the formaldehyde addition, the reaction was kept at about 87° C.for one hour. Then, the reaction mixture was heated to reflux for atotal of 12 hours. At the end of the reflux, the reaction mass was about101° C.

The reaction mass was diluted with 100.1 g more A-150 solvent. Thereactor was then heated and the temperature target was set to 145° C. toremove the water, and was kept at about 145° C. for about 10 hours untila total of 33.9 g of the lower layer was removed. The crude reactionmass contained 3.8 wt % PTBP.

The GPC results of the crude reaction mass are shown in FIG. 3. With atheoretical reaction mass of 324.2 g (assuming all water fromformaldehyde solution and produced from the reaction were removed; andall excess formaldehyde was removed), the crude reaction mass contained3.82 wt % free PTBP (which corresponds to 12.38 g or 11.0 mol % ofunreacted PTBP).

The ¹H-NMR results of the crude reaction mass are shown in FIG. 4. Theyields of the cyclic phenolic resins were determined by further analysisof the ¹H-NMR results of the crude reaction mass, using the calculationmethodology discussed in Example 1.

The analysis results of the ¹H-NMR in FIG. 4 are as follows.

Integrals for calixarene phenolic OH protons (for 1.051 all calixarenes)Integrals for two protons of all methylene bridges 2.567 (cyclic andlinear resins) Integrals for one proton of all methylene bridges 1.2835(cyclic and linear resins) Ratio of calixarene phenolic OH protons tothe 1.051/1.2835 = 81.9% protons of all methylene bridgesTaking into account the 11.0 mol % unreacted PTBP in the yieldcalculation (i.e., 89.0 mol % of the PTBP had reacted) resulted in acrude calixarene yield of 72.9% (i.e., 81.9%×0.89). That is to say, thetheoretical yield of all cyclic components in this crude reaction masswas 72.9%.

Applying the same calculation for the tert-butylcalix[8]arene providedthe following results.

Integrals for tert-butylcalix[8]arene phenolic 1.000 OH protonsIntegrals for one proton of all methylene bridges 1.2835 (cyclic andlinear resins) Ratio of tert-butylcalix[8]arene phenolic OH 1.000/1.2835= 77.9% protons to the protons of all methylene bridgesTaking into account the 11.0 mol % unreacted PTBP in the yieldcalculation resulted in a crude tert-butylcalix[8]arene yield of 69.3%(i.e., 77.9%×0.89). That is to say, the theoretical yield oftert-butylcalix[8]arene in this crude reaction mass was 69.3%.

This crude reaction mass obtained above was then cooled to about 80° C.,and was easily filtered through a Buechner funnel. The filter cake wassuccessively washed with portions of A-150 (a total of 102.8 g) toresult in a wet filter cake. After drying in vacuum at 130° C., theproduct tert-butylcalix[8]arene was obtained in an isolated yield of72.2% (theoretical yield), with an HPLC purity of 98.8% (area % at 281nm) and less than 0.05 wt % PTBP (GC).

Example 3. Synthesis of tert-butylcalix[8]arenes UsingTetramethylammonium Hydroxide (TMAOH) as the Catalyst andParaformaldehyde as the Aldehyde Source

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, Dean-Stark trap, and condenser was loaded with 112.62 gPTBP briquettes (0.75 mol), 22.68 g paraformaldehyde (0.755 mol), and204.65 g xylene. The azeo receiver was filled with 27.3 g xylene. Agentle nitrogen flow was applied on the surface of the reaction masswhile stirring was switched on at 150 rpm. A 5.51 g TMAOH solution (25wt % in methanol, 0.015 mol) was added at a low temperature.

The reaction mixture was then heated, and reflux (when xylene formedazeotropes with the formed water) was observed at ˜119° C.

About 2.5 hours after heating was started, the temperature of thereaction mass reached about 140° C., and was kept for about 10.5 hoursto remove the formed water as completely as possible. Eventually, atotal of 17.35 g lower layer (water) was removed from the Dean-Starktrap. The crude reaction mass contained 4.92 wt % free PTBP as well as58.9 wt % xylene. The GPC results of the crude reaction mass are shownin FIG. 5. The ¹H-NMR results of the crude reaction mass are shown inFIG. 6.

This crude reaction mass was then cooled to ˜80° C., and was easilyfiltered through a Buechner funnel. The filter cake was successivelywashed with five portions of xylene (a total of 533.1 g) to result in afilter cake with 0.12 wt % free PTBP and 8.94 wt % xylene. After drying,the product tert-butylcalix[8]arene was obtained in an isolated yield of69.3% (of theoretical yield), with an HPLC purity of 95.2% (area % at281 nm) and possibility of 2.9% tert-butylcalix[9]arene as a sideproduct, and 0.08 wt % PTBP (GC).

Example 4. Synthesis of tert-amylcalix[8]arenes UsingTetramethylammonium Hydroxide (TMAOH) as the Catalyst

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, overhead addition tank, moisture trap, and condenser wasloaded with 123.2 g para-tert-amylphenol (PTAP) briquettes (0.75 mol)and 90.1 g A-150 (Solvesso™ 150 Fluid). A gentle nitrogen flow wasapplied on the surface of the hot reaction mass and the reactor washeated to about 90° C. When all the PTAP and the A-150 formed a clearsolution, 5.5 g of TMAOH solution (25 wt % in methanol, 0.015 mol) wasadded dropwise at a temperature of 89.3° C. over the course of 3minutes, and this temperature was hold for 60 minutes. At 89.6° C., atotal of 51.4 g of 50 wt % formaldehyde solution (0.86 mol) was addedwithin 18 minutes.

After the formaldehyde addition, the reaction was kept at 90° C. for1.75 hours. The reaction mixture was then heated to reflux at about 99°C. for a total of 12 hours. At the end of the reflux, the reaction masswas at 99.9° C.

The reaction mass was diluted with 70.2 g more A-150 solvent and theempty leg of the azeo trap was filled with 24.5 g A-150. The reactor wasthen heated and the temperature target was set to 145° C. to remove thewater. A lower layer of 13.1 g was removed at 118.2° C. About 62 minutesafter the heating was started, the temperature of the reaction massreached about 145° C., and was kept for about 10 hours until a total of30.8 g of the lower layer was removed (not all the water/methanol hadcome out). The crude reaction mass contained 1.3 wt % PTAP as well as48.5 wt % A-150.

The GPC results of the crude reaction mass are shown in FIG. 7.Theoretically, the solid content of the crude reaction mass wascalculated to be 45.2 wt % (assuming all water from formaldehydesolution and produced from the reaction were removed; all methanol wasremoved; and all excess formaldehyde was removed). The crude reactionmass contained 1.3 wt % free PTAP (which corresponds to 3.8 g or 3.1 mol% of unreacted PTAP).

The ¹H-NMR results of the crude reaction mass are shown in FIG. 8. Theyields of the cyclic phenolic resins were determined by further analysisof the ¹H-NMR results of the crude reaction mass, using the calculationmethodology discussed in Example 1. It was understood that the ¹H-NMRdoes not allow the quantification of the free monomer content; but theGPC results of the final reaction mass display all components in thereaction mass (with their respective resonances at the picked wavelength(here 280 nm)).

The analysis results of the in FIG. 8 are as follows.

Integrals for calixarene phenolic OH protons (for 0.075 all calixarenes)Integrals for two protons of all methylene bridges 0.181 (cyclic andlinear resins) Integrals for one proton of all methylene bridges 0.0905(cyclic and linear resins) Ratio of calixarene phenolic OH protons tothe 0.075/0.0905 = 82.9% protons of all methylene bridgesTaking into account the 3.1 mol % unreacted PTAP in the yieldcalculation (i.e., 96.9 mol % of the PTAP had reacted) resulted in acrude calixarene yield of 80.3% (i.e., 82.9%×0.969). That is to say, thetheoretical yield of all cyclic components in this crude reaction masswas 80.3%.

Applying the same calculation for the tert-amylcalix[8]arene providedthe following results.

Integrals for tert-amylcalix[8]arene phenolic 0.073 OH protons Integralsfor two protons of all methylene bridges 0.181 (cyclic and linearresins) Integrals for one proton of all methylene bridges 0.0905 (cyclicand linear resins) Ratio of tert-amylcalix[8]arene phenolic OH0.073/0.0905 = 80.7% protons to the protons of all methylene bridgesTaking into account the 3.1 mol % unreacted PTAP in the yieldcalculation resulted in a crude tert-amylcalix[8]arene yield of 78.2%(i.e., 80.7%×0.969). That is to say, the theoretical yield oftert-amylcalix[8]arene in this crude reaction mass was 78.2%. This isclose to the observed isolated yield.

This crude reaction mass obtained above was then cooled to about 80° C.,and was easily filtered through a Buechner funnel. The filter cake wassuccessively washed with three portions of A-150 (a total of 454.3 g) toresult in a wet filter cake with 0.3 wt % free PTAP and 6.9 wt % A-150.After drying, the product tert-amylcalix[8]arene was obtained in anisolated yield of 76.6% (theoretical yield), with an HPLC purity of99.3% (area % at 281 nm).

Example 5. Synthesis of tert-octylcalix[8]arenes UsingTetraethylammonium Hydroxide (TEAOH) as the Catalyst

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, overhead addition tank, moisture trap, and condenser wasloaded with 154.7 g para-tert-octylphenol (PTOP) briquettes (0.75 mol)and 89.6 g A-150 (Solvesso™ 150 Fluid). A gentle nitrogen was applied onthe surface of the hot reaction mass and the reactor was heated to about90° C. When all the PTOP and the A-150 formed a clear solution, 5.5 g ofa 40% solution of TEAOH (40 wt % in water, 0.015 mol) was added dropwiseat a temperature of 92.1° C. over the course of 5 minutes, and thistemperature was hold for 100 minutes. At 90.1° C., a total of 50.5 g of50 wt % formaldehyde solution (0.84 mol) was added within 23 minutes.

After the formaldehyde addition, the reaction was kept at 90° C. for 1hour. The reaction mixture was then heated to reflux at about 100° C.for a total of 12 hours. At the end of the reaction, the reaction masswas about 100° C.

The reaction mass was diluted with 13.5 g more A-150 solvent and theempty leg of the azeo trap was filled with 24.4 g A-150. The reactor wasthen heated and the temperature target was set to 145° C. to remove thewater. A lower layer of 16.9 g was removed at 120.5° C. About 1.75 hoursafter the heating was started, the temperature of the reaction massreached about 145° C., and was kept for about 10 hours until a total of36.3 g of the lower layer was removed (not all the water/methanol hadcome out). The crude reaction mass contained 1.4 wt % PTOP as well as37.9 wt % A-150.

The GPC results of the crude reaction mass are shown in FIG. 9.Theoretically, the solid content of the crude reaction mass wascalculated to be 60.85 wt % (assuming all water from formaldehydesolution and produced from the reaction were removed; and all excessformaldehyde was removed). The crude reaction mass contained 1.4 wt %free PTOP (which corresponds to 3.8 g or 2.4 mol % of unreacted PTOP).

The ¹H-NMR results of the crude reaction mass are shown in FIG. 10. Theyields of the cyclic phenolic resins were determined by further analysisof the ¹H-NMR results of the crude reaction mass, using the calculationmethodology discussed in Example 1. It was understood that the ¹H-NMRdoes not allow the quantification of the free monomer content; but theGPC results of the final reaction mass display all components in thereaction mass (with their respective resonances at the picked wavelength(here 280 nm)).

The analysis results of the ¹H-NMR in FIG. 10 are as follows.

Integrals for calixarene phenolic OH protons (for 0.084 all calixarenes)Integrals for two protons of all methylene bridges 0.210 (cyclic andlinear resins) Integrals for one proton of all methylene bridges 0.105(cyclic and linear resins) Ratio of calixarene phenolic OH protons tothe 0.084/0.105 = 80.0% protons of all methylene bridgesTaking into account the 2.4 mol % unreacted PTOP in the yieldcalculation (i.e., 97.6 mol % of the PTOP had reacted) resulted in acrude calixarene yield of 78.1% (i.e., 80.0%×0.976). That is to say, thetheoretical yield of all cyclic components in this crude reaction masswas 78.1%.

Applying the same calculation for the tert-octylcalix[8]arene providedthe following results.

Integrals for tert-octylcalix[8]arene phenolic 0.078 OH protonsIntegrals for two protons of all methylene bridges 0.210 (cyclic andlinear resins) Integrals for one proton of all methylene bridges 0.105(cyclic and linear resins) Ratio of tert-octylcalix[8]arene phenolic OH0.078/0.105 = 74.3% protons to the protons of all methylene bridgesTaking into account the 2.4 mol % unreacted PTOP in the yieldcalculation resulted in a crude tert-octylcalix[8]arene yield of 72.5%(i.e., 74.3%×0.976). That is to say, the theoretical yield oftert-octylcalix[8]arene in this crude reaction mass was 72.5%.

This crude reaction mass obtained above was then cooled to about 80° C.,and was easily filtered through a Buechner funnel. The filter cake wassuccessively washed with three portions of A-150 (a total of 452.3 g),and dried in the vacuum oven to result in a producttert-octylcalix[8]arene in an isolated yield of 64.6% (theoreticalyield), with an HPLC purity of 98.9% (area % at 281 nm), and less than0.05 wt % free PTOP and 0.13 wt % A-150.

Example 6. Synthesis of tert-butylcalix[8]arene UsingTetramethylammoniumhydroxide (TMAOH) as the Catalyst in Diphenylether

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple (having a gas inlet, through which nitrogen stream can beapplied), and condenser was loaded with 112.34 g PTBP briquettes (0.75mol) and 108.25 g diphenylether. A gentle nitrogen flow was on thesurface of the hot reaction mass and the reactor was heated to about 80°C. within 20 minutes. Mixing was set to 200 rpm. Five minutes later,when all the PTBP and diphenylether formed a clear solution, 5.5 g TMAOHsolution (25% in methanol, 0.015 mol) was added dropwise throughaddition funnel at a temperature of 89° C. The reaction mixture washeated to 90° C. and 49.7 g of 50 wt % formaldehyde solution (0.83 mol)was added through the addition funnel within 30 minutes, while theformaldehyde solution was heated periodically with a heat gun to preventformaldehyde from solidification.

Fifteen minutes after the end of the formaldehyde addition, thetemperature was increased to 100° C., the nitrogen flow was decreasedwhile the circulating cooling water flow was increased to combat extramoisture in the condenser, and the conditions were held for 12 hours. Atthe end of the reflux, the reaction mass was about 100° C.

The condenser was then exchanged against a Dean-Stark trap which wasleft empty. The condenser was placed on top of the Dean-Stark trap, thetemperature target was set to 110° C., and the stirring speed was set to200 rpm. The heating was then started to remove the water. The reactortemperature reached 111° C. after 72 minutes, and 140.6 g morediphenylether was added to the reactor. A 21.2 g water layer was removedfrom the side arm of the Dean-Stark trap seven minutes later. Thereaction mass was then heated to 120° C. and, after an additional fortyminutes, to 130° C. The reaction mass became foamy and the heatingblanket, which was covering the upper parts of the flask, was loosened.This foam was likely from the dissolved water in diphenylether, whichevaporated 25 minutes later, and the heating was increased to 135° C.The nitrogen stream over the surface of the reaction mass was slightlyenhanced to facilitate further water removal. Two hours later, thetemperature was increased to 140° C. and continued for 1.5 more hours,until a total of 35.06 g of the lower layer was removed (theoretically,the lower layer should be 43.3 g). The distillation was resumed at 140°C. and subsequently increased to 160° C. over the course of 7 hours.Only 0.97 g more distillate was obtained (a total of 36.03 g). The crudereaction mass contained 1.13 wt % free PTBP.

The GPC results of the crude reaction mass are shown in FIG. 11.Theoretically, the solid content of the crude reaction mass wascalculated to be 32.65 wt % (assuming all water from formaldehydesolution and produced from the reaction were removed; and all excessformaldehyde was removed). The crude reaction mass contained 1.13 wt %free PTBP (which corresponds to 4.15 g or 3.7 mol % of unreacted PTBP.

The ¹H-NMR results of the crude reaction mass are shown in FIG. 12. Theyields of the cyclic phenolic resins were determined by further analysisof the ¹H-NMR results of the crude reaction mass, using the calculationmethodology discussed in Example 1. It was understood that the ¹H-NMRdoes not allow the quantification of the free monomer content; but theGPC results of the final reaction mass display all components in thereaction mass (with their respective resonances at the picked wavelength(here 280 nm)).

The analysis results of the ¹H-NMR in FIG. 12 are as follows.

Integrals for calixarene phenolic OH protons (for 1.077 all calixarenes)Integrals for two protons of all methylene bridges 2.423 (cyclic andlinear resins) Integrals for one proton of all methylene bridges 1.2115(cyclic and linear resins) Ratio of calixarene phenolic OH protons tothe 0.077/1.2115 = 88.9% protons of all methylene bridgesTaking into account the 3.7 mol % unreacted PTBP in the yieldcalculation (i.e., 96.3 mol % of the PTBP had reacted) resulted in acrude calixarene yield of 85.6% (i.e., 88.9%×0.963). That is to say, thetheoretical yield of all cyclic components in this crude reaction masswas 85.6%.

Applying the same calculation for the tert-butylcalix[8]arene providedthe following results.

Integrals for tert-butylcalix[8]arene* phenolic 1.054 OH protonsIntegrals for two protons of all methylene bridges 2.423 (cyclic andlinear resins) Integrals for one proton of all methylene bridges 1.2115(cyclic and linear resins) Ratio of tert-butylcalix[8]arene phenolic OH1.054/1.2115 = 87.0% protons to the protons of all methylene bridges *Asshown in the HPLC analysis below, a small amount oftert-butylcalix[9]arene side product presented in this sample. Thus, the¹H-NMR peaks for tert-butylcalix[8]arene presumably also includedtert-butylcalix[9]arene.Taking into account the 3.7 mol % unreacted PTBP in the yieldcalculation resulted in a crude tert-butylcalix[8]arene yield of 83.8%(i.e., 87.0%×0.963). That is to say, the theoretical yield oftert-butylcalix[8]arene in this crude reaction mass was 83.8%. This isclose to the actual isolated yield of 84.2%.

This crude reaction mass obtained above was then cooled down and waseasily filtered through a Buechner funnel. The filter cake wassuccessively washed with three portions of ethylacetate (100 g eachportion). After drying, a white filter cake was obtained, showing thefollowing compositions: 0.12 wt % PTBP, 4.81 wt % diphenylether and 0.18wt % ethylacetate. The HPLC analysis (which did not account for solventsand unreacted alkylphenols) showed a purity of 92.3% (area % at 281 nm)of tert-butylcalix[8]arene and 5.14% (area % at 281 nm) of a sideproduct believed to be tert-butylcalix[9]arene. The isolated yield was84.2%.

Example 7. Synthesis of tert-butylcalix[8]arene Using DBU as theCatalyst—Kinetic Mechanism for the Reaction Described in Example 1

A 2 L round bottom flask, equipped with an overhead stirrer,thermocouple (having a gas inlet, through which nitrogen stream can beapplied), and condenser, was loaded with 550.2 g PTBP briquettes (3.66mol) and 367.0 g A-150 (Solvesso™ 150 Fluid). A gentle nitrogen flow wasapplied on the surface of the hot reaction mass and the reactor washeated to about 80° C. within 20 minutes. Mixing was set to 112 rpm.Five minutes later, when all the PTBP and A-150 formed a clear solution,8.6 g DBU (98%, 0.056 mol) was added dropwise at a temperature of 81°C., and a slight exotherm was observed. The reaction mixture was heatedto 85° C. and 220 g of 50 wt % formaldehyde solution (3.66 mol) wasadded within 1 hour and 20 minutes, while the formaldehyde solution washeated periodically with a heat gun to prevent formaldehyde fromsolidification.

After the formaldehyde addition, the temperature was increased to 90°C., the nitrogen flow was decreased while the circulating cooling waterflow was increased to combat extra moisture in the condenser, and theconditions were held for 30 minutes. A formaldehyde trap was placedunder the condenser, with the arm to the trap wrapped with aluminumfoil, and was heated to reflux at 100° C. about 40 minutes after theformaldehyde addition. The heating of the reaction mixture continued andthe total reflux time was 15.25 hours at a temperature of about 100-105°C. (under reflux). At various points of the reflux stage, samples of thereaction mass were taken to evaluate the content of free formaldehyde: asample taken after heating for about two more hours at 102° C. showed3.0% free formaldehyde; a sample taken after additional heating forabout two more hours at 102° C. and about 25 minutes at 103° C. showed3.0% free formaldehyde; a sample taken after additional heating forabout 35 minutes at 102-103° C. and about 7.5 hours at 102-105° C.showed 2.3% free formaldehyde; and a final sample taken after additionalheating for about 2 hours at 102-105° C. showed 2.5% free formaldehyde.

The heating was switched off and the formaldehyde trap was exchangedagainst a Dean-Stark trap which was filled with A-150. The condenser wasplaced on top of the Dean-Stark trap and the heating was resumed toremove the water in the reaction system. Fifty seven minutes after thereflux ended, the heating was set to 115° C. and 54.5 g additional A-150was added to the reaction flask, and the temperature was furtherincreased. One hundred and twenty minutes after the reflux ended, atotal of 128.9 g water layer was removed and the reaction temperaturereached 145.3° C. The distillation was continued while the temperaturewas kept at about 145° C. The reaction mass became thicker and thicker.At the end of distillation, the highly viscous reaction mass was pouredinto glass jars. A final total lower distillate layer (water layer) of167.2 g was observed. The total distillation time was 6.5 hours. Atvarious points of the distillation stage, samples of the reaction masswere taken to evaluate the composition of the reaction product, inparticular the content of tert-butylcalix[8]arene. The first sample (t0)was taken 22 minutes after the reflux ended. The second sample (t1) wastaken after a total of 42 g water layer was removed. The third sample(t2) was taken after a total of 88 g water layer was removed. The fourthsample (t3) was taken after a total of 128.9 g water layer was removed.The next few samples were taken hourly after the temperature reached145° C.: t4 at the first hour, t5 at the second hour, t6 at the thirdhour, and t7 at the fourth hour. A final sample (tF) was taken when theheating was switched off.

The GPC results (Mw=1395) of the final reaction mass (taken from thefinal sample, tF) are shown in FIG. 13. FIG. 13 shows that the reactionproduct had a very lean and sharp peak. The final reaction masscontained 2.36% free PTBP and less than 15 ppm free formaldehyde.

Table 1 lists the ¹H-NMR results for the samples of the reaction mass atvarious distillation stages and temperatures. The ¹H-NMR features of thetert-butylphenol-derived calixarenes from ring size 4 to ring size 16,such as the proton signals of the methylene bridges and of the phenolichydroxyls in CDCl₃, have been discussed in an article entitled“Isolation, Characterization, and Conformational Characteristics ofp-tert-butylcalix[9-20]arenes” by Stewart et al. published on J. Am.Chem. Soc. 121: 4136-46 (1999) (“Stewart”), which is hereby incorporatedby reference in its entirety, to the extent not inconsistent with thesubject matter of this disclosure. That article shows that onlytert-butylcalix[4]arenes and tert-butylcalix[8]arenes display a set oftwo doublets (at 20° C.) for their methylene bridges; and they showdifferent resonances for the phenolic OH groups (at 20° C.):tert-butylcalix[4]arene has a resonance at about 10.4 ppm whiletert-butylcalix[8]arene displays it at about 9.6 ppm.

The ¹H-NMR results of a few samples of the reaction mass at variousdistillation stages and temperatures are shown in FIGS. 14A-14C forillustrative purposes. For instance, FIG. 14A shows that in sample t0,taken at the end of the reflux and the beginning of the water removalphase, only 13.9% of all resin components had turned intotert-butylcalix[6 & 8]arenes (the value was taken from the integrals ofthe phenolic hydroxyl protons of tert-butylcalix[6 & 8]arene(respectively one methylene proton of tert-butylcalix[8]arene) dividedby all protons coming from the reaction with formaldehyde—calculatedhere by adding the values of the second column and the ninth column, anddividing by the value of the fourth column: (0.019+0.003)/0.158), asshown in Table 1). As shown in Table 1, at this point of the reaction,the selectivity between calix[8]arene and calix[6]arene is not yet great(relative ratio between integrals of tert-butyl calix[6]arene andcalix[8]arenes hydroxyl protons is 10.7% (neglecting integration errorcoming from AA)). As shown in Table 1, the selectivity toward thetert-butylcalix[8]arene developed during the six hours of water removalstep, i.e., relative ratio between integrals of tert-butyl calix[6]areneand calix[8]arenes went from 10.7% at 0 hour of distillation to 3.4%after 3-4 hours of distillation, and to 1.3% after 5-6 hours ofdistillation.

FIG. 15 plots the data taken from Table 1, particularly, %tert-butylcalix [8]arene of total reaction products and the reactortemperature against the time of the water removal, showing the kineticsduring the water removal phase for the formation oftert-butylcalix[8]arene.

An intermediate, denoted as

7,13,19,25-tetra-tert-butyl-27,28,29,20-tetrahydroxy-2,3-bishomo-3-oxacalix[4]arene;¹H-NMR (CDCl₃): 9.60 ppm (2 OH on ring B and C), 8.92 ppm (2 OH on ringA and D); see Gutsche et al., “Calixarenes. 4. The synthesis,characterization, and properties of the calixarenes fromp-tert-butylphenol, J. Am. Chem. Soc. 103: 3782-92 (1981), which ishereby incorporated by reference in its entirety, to the extent notinconsistent with the subject matter of this disclosure) was present inthe ¹H-NMR of the sample Nos. t0-t5, and was present in a trace amountin the ¹H-NMR of the sample No. t6, but was not observed in the ¹H-NMRof the sample No. tF, i.e., the analytical data shows that the finalreaction product after 6.5 hours of water removal did not contain thisreaction intermediate.

A column chromatography was conducted on the final reaction mass, toseparate the calixarene from the linear resins to assess the purity ofthe obtained cyclics by means of HPLC (the cyclic compounds need to beseparated from the linear resin to avoid interfering with each other onthe HPLC column), and to calculate the yield of the calixarenecompounds.

Briefly, 0.774 g of sample tF was dissolved in chloroform and placed ona chromatography column (12 g, Aldrich, high purity grade, pore size 60Å, 200-400 mesh particle size). The sample was eluted with chloroforminitially and followed by a mixed solvent of acetone:methanol:chloroform(1:1:1 by volume). In the initial fractions, the cyclic compounds ranthrough (the isolated cyclic sample tC) while the linear compoundsremained on top. The switch to the mixed solvent then eluted the linearpartition through the column. The chromatographic separation wascontrolled via TLC plates (coated with UV absorbance) and then therespective fractions were combined and concentrated to dryness at theRotavap (final conditions: 1 mbar, 50° C., for 30 minutes).

The solid content of the final calixarene reaction mass tF wasdetermined to be 68.2% (˜1 g sample, 200° C. for 30 minutes).

The ¹H-NMR results for the cyclic sample tC are shown in FIG. 16A. Theresults are also summarized in Table 1.

The TGA (TA Instruments model TGA Q50) results for the cyclic sample tCare shown in FIG. 16B. As shown in FIG. 16B, the weight loss until about180° C. may be due to the loss of the incorporated solvent, forinstance, A-150, because calixarenes can incorporate solvents into theirsolid structures, which sometimes cannot be completely removed easily bymeans of vacuum and heat. The major loss around 400° C. appeared to bethe decomposition of the main calixarene, indicating a high thermalstability of the isolated calixarene compounds.

The HPLC results for the cyclic sample tC are shown in FIG. 16C. It wasdetermined from the GC that sample tC contained 15.2 wt % A-150 solvent.Also, the calculation of peak area from the HPLC indicated that thepurity for tert-butylcalix[8]arene (solvent was not integrated) was95.52%.

As a control, the HPLC results for a commercially availabletert-butylcalix[8]arene sample are shown in FIG. 16D.

TABLE 1 The ¹H-NMR results for the samples of the reaction mass atvarious distillation stages (Example 7) Sample Integrals IntegralsRelative No./min for one Integrals for two Integrals Integrals ratiobetween after methylene for phenolic Proton methylene for two forphenolic integrals of tert- start of proton, OH protons, count % tert-protons, methylene OH protons, butylcalix[6] water tert- tert- (4.4ppm + butylcalix[8] resins protons, tert- arene and tert- removalbutylcalix[8] butylcalix[8] ½*3.9 ppm + arene of ° C./g and other with—O- butylcalix[6] butylcalix[8] [min] arene^(a) arene^(b) ½ * 4.9ppm)^(c) total^(d) water out^(e) calixarenes^(f) substitution^(g)arene^(h) arene [%] t0/0 0.019 0.025^(i) 0.158 12.0 104.3/—  0.140 0.1380.003 10.7 t1/— 0.198 0.186^(i) 1.237 16.0  —/42 1.062 1.016 0.023 11.0t2/— 0.024 0.030^(i) 0.1755 13.7 —/8 0.160 0.143 0.004 11.8 t3/98 0.0330.035 0.161 20.5  145.3/128.9 0.141 0.115 0.004 10.3 t4/153 0.049 0.0470.120 40.8   145/135.5 0.093 0.049 0.004 7.8 t5/213 0.114 0.112 0.161570.6 146.5/—  0.069 0.026 0.004 3.4 t6/273 0.094 0.095 0.1265 74.3 145/—0.053 0.012 0.003 3.06 t7/333 0.084 0.079 0.1175 71.5 146/— 0.057 0.0100.001 1.3 tF/343 0.135 0.134 0.1655 81.6   146/167.2 0.053 0.008 0.0010.74 tC/— 0.544 0.548 0.5925 91.8 0.097 0 0.006 1.08 ^(a)Value was takendirectly from the NMR spectrum at about 4.4 ppm ^(b)Value was takendirectly from the NMR spectrum at about 9.66 ppm ^(c)Value was takenfrom the NMR spectrum and calculated using the equation listed in thetable; these are all protons coming from the reaction with formaldehyde:methylols, ethers, methylene bridges in linear resins as well ascalixarenes. Since tert-butylcalix[8]arene splits the methylene bridgeinto two clearly distinct signals (and each can be integrated), the areacount of the other methylene bridging groups areas are divided into halfto account for one of the two protons ^(d)The percentage oftert-butylcalix[8]arene of all products resulted in from the reactionwith formaldehyde can then be calculated by division of the areas forone proton of tert-butylcalix[8]arene by the total value of onemethylene proton of all products resulted in from the reaction withformaldehyde. The value of this column was obtained by dividing thevalue of the second column by the value of the fourth column. Forinstance, for “t0,” 0.019/0.158 = 12.0%. ^(e)The water in the reactionsystem came from formaldehyde (~110 g water from the formaldehydeloading of this example) ^(f)Value was taken directly from the NMRspectrum at about 3.9 ppm ^(g)Value was taken directly from the NMRspectrum at about 4.9 ppm ^(h)Value was taken directly from the NMRspectrum at about 10.56 ppm ^(i)Peak has a tiny, little shoulder (likelyfrom structure AA)

Example 8. Synthesis of tert-butylcalix[8]arene Using TEAOH as theCatalyst—Kinetic Mechanism for the Reaction Described in Example 2

This example discusses the kinetics of the calix[8]arene formation usinga sterically hindered tetraalkyl-ammonium hydroxide as the catalyst. Thereaction scale was chosen that small sampling sizes of the reaction masswould not significantly impact the kinetic behavior of the total batch.The reaction set up was similar to that of Example 1, with the startingmaterial loading as follows: PTBP: 563 g (3.75 mol, 44.4 wt % of totalloading); A-150 (Solvesso™ 150 Fluid): 450 g; 40% aqueoustetraethylammonium hydroxide solution as the catalyst: 30.0 g; 50 wt %formaldehyde solution: 225.5 g (3.75 mol). The total initial loading was1268.5 g. One additional portion of A-150 (67.5 g) was added later inthe reaction system.

At various points of the reflux stage and distillation stage, samples ofthe reaction mass were taken to evaluate the composition of the reactionproduct, in particular the content of tert-butylcalix[8]arene. Becausethe reaction system is triphasic (i.e., it has an aqueous and a stickyaromatic-150 layer including some solids), prior to testing, the samplewas mixed at room temperature with a spatula until homogeneous.

Table 2 lists the ¹H-NMR results for the samples of the reaction mass atvarious times of the reflux phase and distillation phase. As discussedin Example 7, the ¹H NMR features of the tert-butylphenol-derivedcalixarenes from ring size 4 to ring size 16, such as the proton signalsof the methylene bridges and of the phenolic hydroxyls in CDCl₃, werediscussed in Stewart. In general, the proton NMR allows one to analyzecalixarenes reaction masses through their respective phenolic protons(calixarenes), methylene bridges between aromatic units (for linear andcyclic compounds—at about 3.6-3.9 ppm for the linear and most cycliccompounds; for tert-butylcalix[4 & 8]arenes, one doublet at 4.3 ppm (or4.4 ppm for tert-butylcalix[8]arene) and one doublet at 3.5 ppm),methylols (at about 4.4-4.6 ppm), and benzyl ether derivatives (at about4.6-4.9 ppm)

as described in Perrin et al., Supramolecular Chemistry 4:153-57 (1994);see also, Gutsche, “Calixarenes” pages 27-86 (Royal Society ofChemistry, 1989), both of which are hereby incorporated by reference intheir entirety, to the extent not inconsistent with the subject matterof this disclosure. The standard proton NMR does not allow one toquantify the amount of unreacted PTBP in the reaction mass since itsphenolic proton disappeared in the baseline.

Table 2 also lists the results of wt % determinations for the amounts offree formaldehyde and unreacted PTBP present. The determination wasbased on the assumption that no mass was lost during the reflux stage.The ¹H-NMR results of a few samples of the reaction mass at varioustimes of the reflux stage are shown in FIGS. 17A-17D for illustrativepurposes.

It was assumed that the integrals for the signal group around 4.9 ppmcame just from two methylene protons with oxygen substitution; they donot contain areas from the —OH proton (i.e., the —OH protons of themethylol groups do not typically show up in a ¹H NMR spectrum). Theassumption was based on the fact that the experimental spectrum of acompound having two aromatic units connected by a methylene bridge withtwo methylol-groups on both ends

does not have —OH protons of the methylol groups. In addition, similarresults were reported for a compound having three and four aromaticunits connected by a methylene bridge with two methylol groups on bothends (see Dhawan et al., “Calixarenes. 10. Oxacalixarenes,” J. Org.Chem. 48:1536-39 (1983), which is hereby incorporated by reference inits entirety, to the extent not inconsistent with the subject matter ofthis disclosure). All these experiments confirmed the above assumption.

Formaldehyde can react with para-substituted alkylphenols under theapplied reaction conditions basically in three ways: forming a methylenebridge between two aromatic units; forming a substituent on an aromaticnucleus and residing as a methylol compound; or forming a dibenzyletherbridge between two aromatic units. Each of the products formed fromthese methods have a distinct resonance area in the ¹H-NMR, and theirintegrals can be determined.

Based on the above assumption, the degree of di-substitution of thereacted PTBP with formaldehyde can be determined from theweight-percentage determination for the free formaldehyde and free PTBP.Then, the reduced integral value of all methylene protons for singlesubstituted PTBP can be calculated by correcting the observedmethylol/benzyl ether derivative integral around 4.9 ppm for thedi-methylolated contribution, and adding this number to the integrals ofthe protons for the methylene bridge protons for calixarenes and linearresins. This number serves as the basis for further calculations of howmuch of a particular calixarene has formed (i.e., by comparing thisnumber against the integrals for the respective phenolic OH protons ofthe particular calixarene). See, for instance, the results listed inTable 3.

As shown in Table 2, the 1-hour sample contained about 5.4 mol % ofunreacted formaldehyde, and the 12-hour sample still contained 4.1 mol %of unreacted formaldehyde. That is to say, during the reflux phase ofthe initial 12 hours, the free formaldehyde in the reaction mass samplesremained essentially the same, suggesting that all formaldehyde hadbasically reacted during the first hour and no further reaction withformaldehyde occurred during the rest of the reflux stage. Based on thisresult, it was assumed that a total of about 95 mol % of theformaldehyde reacted within the first hour (and throughout the initial12 hours in the reflux phase), and no formaldehyde, or very little, waslost through the condenser.

Moreover, in Table 2, the 1-hour sample contained about 26.4 mol % ofunreacted PTBP, and the 12-hour sample contained about 17.3 mol % ofunreacted PTBP. That is to say, approximately three quarters of theinitial PTBP reacted within the first hour and then a little more PTBPwas consumed during the next 11 hours.

TABLE 2 Analysis of the samples of the reaction mass at various refluxand distillation stages (Example 8) Integrals Free Integrals IntegralsIntegrals for two HCHO PTBP for two Integrals for one for phenolicIntegrals for [wt %]/ [wt %]/ methylene for two methylene phenolicprotons phenolic OH [g]/ [g] protons, methylene Sample proton, tert- OH,tert- of the protons, tert- [mol]/ (% of linear resins protons ReactedTime butylcalix[8] butylcalix[8] four from butylcalix[6] [mol % startingand other with —O- PTBP [hours]^(a1) [° C.] arene^(b) arene^(c) AA^(d)arene⁶ left] PTBP) calixarenes^(f) substitution^(g) [g] 1 102.6 0 0 0 00.48/6.09/  11.7/148.4 0.047 0.248 414.6/73.6 0.20/5.4 (26.4%) mol %reacted 2 0.00 0.001^(h) 0.001 0 0.58   10/126.9 0.064 0.316 436.1(22.5%) 3 102.9 0.001^(h) 0.001 0 0.46 10.8/137.0 0.071 0.267 426(24.3%) 4 102.4 0.002 0.003 0.001 0.000 0.43 10.1/128.1 0.086 0.193434.9 (22.8%) 5 102.3 0.003 0.004 0.001 0 0.42 9.07/115.1 0.099 0.178447.9 (20.4%) 6 102.6 0.006 0.006 0.002 0.001 0.44 9.55/121.1 0.12 0.174441.9 (21.5%) 7 101.9 0.012 0.007 0.001 0.001 0.26 9.46/120.0 0.1480.169 443 (21.3%) 8 102.3 0.006 0.009 0.004 0.001 0.41 7.05/89.4  0.1170.160 473.6 (15.9%) 9 102.1 0.014 0.012 0.002 0.002 0.40 8.73/110.70.152 0.146 452.3 (19.7%) 10 101.9 0.019 0.013 0.001 0.001 0.388.07/102.4 0.162 0.149 460.6 (18.2%) 11 101.6 0.018 0.018 0.002 0.0020.38 7.64/96.9  0.154 0.128 466.1 (17.2%) 12 103.8 0.021 0.019 0.0030.003 0.36/4.57/ 7.86/97.4  0.159 0.129 465.6/82.7 0.15207/4.05 (17.3%)mol % reacted Start to distill [° C.]/ total ml Integrals Integralsdistilled Integrals Integrals for two Integrals for Free PTBP for twoIntegrals out [g]^(i)/ for one for phenolic phenolic phenolic OH HCHO[wt %]/ methylene for two therefore methylene OH protons, protonsprotons, [wt %]/ [g] protons methylene Sampling remaining proton, tert-tert- of the tert- [g]/ (% of linear resins protons Reacted time mass inbutylcalix[8] butylcalix[8] four from butylcalix[6] [mol]/ starting andother with —O- PTBP [hours]^(a2) flask^(j) [g] arene^(b) arene^(c)AA^(d) arene^(e) [mol %] PTBP) calixarenes^(f) substitution^(g) [mol %]I, 12.25 105.1/29/ 0.027 0.026^(h) 0.003 0.003 0.28 8.05/99.78/17.70.186 0.133 82.3 1239.5 II, 12.42 107.8/99/  0.14^(k) 8.48/99.17/17.682.4 1169.5 III, 12.50 115.2/124/ 0.025 0.020 0.003 0.003 0.078.75/106.1/18.8 0.180 0.127 81.2 1212.7¹ IV, 12.58 130/131/ 0.068.12/97.9/17.4 82.6 1205.7 V, 12.67 145/135/ 0.033 0.025 0.002 0.0030.06 7.88/94.7/16.8 0.169 0.109 83.2 1201.7 A, 13.67 145/145/ 0.0650.000 0.003 0.03 5.36/63.9/11.3 0.207 0.044 88.7 1191.7 B, 14.67145.5/148/ 0.048 0.047^(h) 0.001 0.001  70 ppm 4.35/51.7/9.2 0.157 0.02290.8 1188.7 C, 15.67 145/150/ 0.054 0.053 0.000 0.001 <15 ppm3.97/47.1/8.4 0.157 0.007 91.6 1186.7 D, 16.67 145.6/150/ 0.086 0.0840.001 0.001  60 ppm 3.89/46.2/8.2 0.222 0.006 91.8 1186.7 E, 17.17145/152/ 0.078 0.080 0.000 0.001 <15 ppm 3.71/44.0/7.8 0.200 0.002 92.21184.7 Final 0.105 0.106 0.000 0.001 <15 ppm 3.88 0.266 0 ^(a1)Samplingtime: number of hours after the end of the formaldehyde addition andreaching reflux ^(a2)Sampling time: number of hours after the end of theformaldehyde addition; I-V indicate different stages of distillationstage when heating to 145° C.; A-E indicate different stages ofdistillation stage after reaching 145° C. ^(b)Value was taken directlyfrom the NMR spectrum at about 4.4 ppm ^(c)Value was taken directly fromthe NMR spectrum at about 9.66 ppm ^(d)Value was taken directly from theNMR spectrum at about 9.01 ppm ^(e)Value was taken directly from the NMRspectrum at about 10.56 ppm ^(f)Value was taken directly from the NMRspectrum at about 3.9 ppm ^(g)Value was taken directly from the NMRspectrum at about 4.9 ppm ^(h) Peak has a tiny, little shoulder (likelyfrom structure AA) ^(i) ml assumed as gram ^(j) The weight of thesamples were not taken into account ^(k) Formaldehyde distills out -assuming that the formaldehyde consumption was 95% in the first hour anddid not change ^(l) The second portion of 68.2 g A-150 was added

TABLE 3 Analysis of the samples of the reaction mass at various refluxand distillation stages (Example 8) Integrals Integrals for one forphenolic methylene OH photons, Calculated Integrals proton tert- tert-molar for two butylcalix[8] butylcalix[6] PTBP ratio of methylenearene^(b)/ a rene^(d)/ Free HCHO [wt %]/[g] reacted protons, Sample [%from [% from [wt %]/[g]/ (% of HCHO to linear Time/ total reacted totalreacted [mol]/[mol % starting reacted resins and [min]^(a) PTBP^(c)]PTBP^(c)] left] PTBP) PTBP calixarenes^(e) 1  0/0 0    0.48/6.09/11.7/148.4 1.291 0.047 0.20/5.4  (26.4%) 2 0.00/0   0/0 0.58   10/126.91.226 0.064 (22.5%) 3  0/0 0.46 10.8/137.0 1.255 0.071 (24.3%) 40.002/1.6  0.000/0  0.43 10.1/128.1 1.231 0.086 (22.8%) 5 0.003/2.4  0/0 0.42 9.07/115.1 1.193 0.099 (20.4%) 6 0.006/4.5  0.001/0.8 0.449.55/121.1 1.210 0.12 (21.5%) 7 0.012/8.3  0.001/0.7 0.26 9.46/120.01.207 0.148 (21.3%) 8 0.006/4.6  0.001/0.8 0.41 7.05/89.4  1.130 0.117(15.9%) 9 0.014/10.2 0.002/1.5 0.40 8.73/110.7 1.183 0.152 (19.7%) 100.019/13.1 0.001/0.7 0.38 8.07/102.4 1.161 0.162 (18.2%) 11 0.018/13.50.002/1.5 0.38 7.64/96.9  1.147 0.154 (17.2%) 12 0.021/15.5 0.003/2.20.36/4.57/ 7.86/97.4  1.149 0.159 0.15/4.05 (17.3%) I 0.027/17.9 0.0030.28 8.05/99.78/17.7 1.154 0.186 II  0.14^(i) 8.48/99.17/17.6 1.153 III0.025/17.3 0.003 0.07 8.75/106.1/18.8 1.170 0.180 IV 0.06 8.12/97.9/17.4 1.150 V 0.033/25.0 0.003 0.06  7.88/94.7/16.8 1.1420.169 A 0.065/52.4 0.003 0.03  5.36/63.9/11.3 1.071 0.207 B 0.048/53.90.001  70 ppm  4.35/51.7/9.2 1.046 0.157 C 0.054/60.7 0.001 <15 ppm 3.97/47.1/8.4 1.037 0.157 D 0.086/70.4 0.001  60 ppm  3.89/46.2/8.21.035 0.222 E 0.078/77.2 0.001 <15 ppm  3.71/44.0/7.8 1.030 0.200 Final0.105 0.001 <15 ppm 3.88 0.266 Sum^(h) of % of all Sum of correctedintegrals for methylol/benzyl integrals for two corrected one ethersprotons Corrected methylene protons methylene proton Integrals in thetotal integrals with —O- with —O- for two reacted for twosubstitution^(g) + substitution^(g) + methylene material in methyleneintegrals for two integrals for one Sample protons relation to allproton methylene protons methylene proton Time/ with —O- reacted PTBPwith —O- resins and from linear resins [min]^(a) substitution^(f) [mol%] substitution^(g) calixarenes^(e) and calixarenes^(e) 1 0.248 103.80.192 0.239 0.1195 2 0.316 98.1 0.258 0.322 0.161 3 0.267 94.0 0.2130.284 0.142 4 0.193 79.4 0.157 0.243 0.1215 5 0.178 71.8 0.149 0.2480.124 6 0.174 66.9 0.144 0.264 0.132 7 0.169 58.7 0.140 0.288 0.144 80.160 61.8 0.142 0.259 0.1295 9 0.146 53.1 0.123 0.275 0.1375 10 0.14951.4 0.128 0.290 0.145 11 0.128 48.1 0.112 0.266 0.133 12 0.129 47.60.112 0.271 0.1355 I 0.133 44.2 0.115 0.301 0.1505 II III 0.127 43.90.109 0.289 0.1445 IV V 0.109 41.3 0.095 0.264 0.132 A 0.044 17.7 0.0410.248 0.124 B 0.022 12.4 0.021 0.178 0.089 C 0.007 4.3 0.007 0.164 0.082D 0.006 2.6 0.006 0.228 0.114 E 0.002 1.0 0.002 0.202 0.101 Final 0^(a)Sampling time: number of hours after the start of water removal; seethe Sample time column in Table 2. ^(b)Value was taken directly from theNMR spectrum at about 4.4 ppm ^(c)Determined from one methylene protonfrom the last column ^(d)Value was taken directly from the NMR spectrumat about 10.56 ppm ^(e)Value was taken directly from the NMR spectrum atabout 3.9 ppm (including from calix[4]arene & calix[8]arene) ^(f)Valuewas taken directly from the NMR spectrum at about 4.9 ppm ^(g)Value wastaken from the NMR spectrum at about 4.9 ppm with no di-substitution^(h)This number excluded di-substitution ^(i)Formaldehyde is distillingout (for the calculations it is assumed that the formaldehydeconsumption was 95% in the first hour and did not change)

The ratio of mono- and di-addition of formaldehyde to the PTBP moleculesin each sample can be calculated by dividing the reacted molar amount offormaldehyde by the reacted molar amount of PTBP, as shown in Table 3.This number is usually greater than 1.0. During the distillation phase,unreacted accessible phenolic aromatic carbons can only react until allthe methylol or dibenzylether groups have disappeared in the ¹H-NMRspectra; only then it can become 1.0. The decimals above 1.0 reflect themolar percentage of reacted PTBP, at which point the reacted PTBPmolecule has bonded with two molecules of formaldehyde. For instance, inthe 1-hour reflux sample, the molar ratio between the reactedformaldehyde and reacted PTBP is 1.291. This means that 29.1 mol % ofthe reacted PTBP molecules had bonded with two molecules offormaldehyde. The integrals of the methylol and dibenzylether protonscan be normalized for “di-substitution” of the alkylphenols that reactedwith formaldehyde. Then, from the integral values obtained from the¹H-NMR spectra, one can calculate a baseline number for all reacted PTBPin the reaction mass. This baseline number can be obtained from theproton NMR, by adding the integrals of the “corrected” methylol anddibenzylether protons and all the integrals of the protons from themethylene bridges of linear and calixarene resin molecules. Thedifferent values for, e.g., the different phenolic protons ofdifferent-sized calixarenes can now be compared against this obtainedcorrected integral sum to estimate their particular concentrations inthe total reaction mass.

In sum, the methylene bridges between the aromatic units in thesecalixarene reaction masses usually reflect the reaction of onealkylphenol with one formaldehyde for the calixarenes. For linearresins, this alkylphenol to formaldehyde ratio holds only if oneterminal aromatic unit is substituted by a methylol group; if the twoterminal aromatic units are not substituted by any methylol groups, thisalkylphenol to formaldehyde ratio will be lower. One needs to correctthe methylene proton integrals of the methylol or dibenzyletherresonance for the amount of alkylphenol having reacted with twomolecules of formaldehyde. This was done by dividing the areas of themethylol/benzylether protons by the molar ratio of the reactedformaldehyde and the reacted alkylphenol. The sum of this corrected areatogether with the area for all the methylene protons would thenapproximately capture the mono-substitution of the alkylphenol reactedwith formaldehyde.

The analysis of the total reacted PTBP (or other alkylphenol startingmaterial) from the integrals in the ¹H-NMR spectra was determined by thefollowing method. The methylene bridge protons between the phenolicunits are typically present at around 3.9 ppm (tert-butylcalix[4 &8]arenes show the doublets at around 4.4 (4.3 fortert-butylcalix[4]arene) and 3.5 ppm). The methylene protons of theoxygen-substituted protons of the methylene group at the aromatic unitare typically present between 4.5-5.5 ppm. It was assumed that the sumof the areas of the methylene protons and the correctedmethylols/benzylethers would be representative for all reacted PTBPmolecules, and that this area value can then be used to relate the otherintegrals to obtain the concentration of a particular compound.

Based on the above analyses from the collected ¹H-NMR data and theweight-percentage determination, after normalizing these ¹H-NMR results,the following results are provided in Table 3.

Low-set GPC analyses were also performed for the samples of the reactionmass at various times of the reflux stage and distillation stage, tounderstand the degree and distribution of the calixarene resin formationand their pre-cursors over time, particularly because GPC distinguishesthe molecules by size. The low-set GPC results of two samples are shownin FIGS. 18A-18B to illustrate how the data were collected and resultswere analyzed. FIG. 18A shows the low-set GPC result for the 2-hourreflux sample and FIG. 18B shows the low-set GPC result for the 12-hourreflux sample. It is understood that the linear resins can have zero,one, or two methylol groups at their terminal phenol groups; they canalso contain benzylether linkages in-between the aromatic nuclei. Thesedistinctive linear chains cannot easily be resolved by GPC and the peakswere just grouped as “dimers,” “trimers,” “tetramers,” etc., independentof their methylol/ether substitution pattern. The oligomer compoundslarger than the calix[8]arene are referred to as “[8] plus-region.” Thelow-set GPC results provide area-% (280 nm) as well as M_(w) for eachsegment.

Table 4 summarizes the identified area % (collected at 280 nm) fromthese low-set GPCs as well as the wt % of the PTBP andtert-butylcalix[8]arenes as determined by for the samples of thereaction mass at various times of the reflux stage and distillationstage. Some results were also plotted in FIG. 19.

The final column in this table was derived from the kinetic ¹H-NMR dataand displays how much methylol/benzylether compound is present in allthe formed product at a specific point in time. If allmethylol/benzylether groups have been converted at the end of thereaction, this value would become 0 or as close as possible to 0. Asshown in Table 4 as well as in FIG. 19, during the initial 12 hours ofreflux stage, the percentage of all methylol protons and benzyletherprotons in the total reacted materials in relation to the total reactedPTBP continuously reduced from about 100% to about 47%. A constantreduction in this value indicates a constant disappearing of theterminal methylol groups (or the bridging dibenzylether groups) tobecome the methylene bridges between the phenolic rings, forming thedesired oligomers. During the distillation phase, this value reducedfrom about 47% (after the reflux stage and at the beginning of thedistillation stage) to about 1% at the end of distillation stage (afterabout 5 hours of distillation), indicating that the cyclization towardthe desired calix[8]arene took place, ending up with a high yield/highselectivity calix[8]arene product.

The results of this kinetic model is in contrast to the kineticmechanism observed for the conventional calixarene formation processusing paraform in xylene and an alkaline base as the catalyst (see,e.g., Vocanson et al., “Characterization of synthetic precursors ofp-tert-butylcalix[4]arene and p-tert-butylcalix[8]arene. Mechanisms offormation of calix[4]arene and calix[8]arene,” Supramolecular Chemistry1(7): 19-25 (1996), which is incorporated herein by reference in itsentirety, to the extent not inconsistent with the subject matter of thisdisclosure). While the conventional alkaline base catalysts convert theformaldehyde in a much faster kinetics, the nitrogen-containing basecatalysts allowed for a slower build-up of desirable linear precursorsfor the formation of tert-butylcalix[8]arenes.

TABLE 4 Analysis of the samples of the reaction mass at various refluxand distillation stages (Example 8) percentage of all methylol/benzyldifference ether protons in between the total reacted tetramer +calix[8] calix[8]arene calix[8]arene material in Sample PTBP^(b)methylol dimer trimer pentamer arene calix[8] from GPC plus- relation toall Time/ (by PTBP (by (by (by (by (by arene (by and by region reactedPTBP [hour]^(a) GPC) [wt %] GPC) GPC) GPC) GPC) GPC)^(C) ¹H- NMR) ¹H-NMR(by GPC) ° C. (from ¹H-NMR) 1 22.25 26.4 33.49 13.98 7.2 11.79 0 102.6103.8 2 19.4 22.5 20.6 12.75 8.2 12.99 0 102.6 98.1 3 24.3 102.9 94 416.16 22.8 15.27 10.73 8.65 13.46 1.6 102.4 79.4 5 16.56 20.4 11.74 9.848.83 14.2 2.4 102.3 71.8 6 16.36 21.5 9.95 9.1 8.78 13.78 4.5 102.6 65.97 15.15 21.3 9.49 8.3 8.97 14.01 28.39 8.3 20.09 15.15 101.9 58.7 814.91 15.9 8.21 7.92 9.03 14.33 4.6 102.3 61.8 9 13.93 19.7 7.44 7.218.81 13.02 33.84 10.2 23.64 15.25 102.1 53.1 10 13.94 18.2 6.77 7.139.63 13.84 33.72 13.1 20.62 14.4 101.9 51.4 11 12.68 17.2 6.51 6.36 8.8213.73 36.68 13.5 23.18 14.51 101.6 48.1 12 12.22 17.3 6.25 5.99 8.8313.74 36.84 15.5 21.34 15.62 103.8 47.6 12.25 15.19 8.05 5.96 8.87 13.9337.17 17.9 19.27 15.19 105.1 44.2 12.43 17.8 8.48 5.84 8.79 13.27 38.715.07 107.8 12.5 17.63 8.75 5.73 8.7 13.69 38.34 17.3 21.54 15.37 115.243.9 12.58 17.15 8.12 5.59 8.53 13.21 39.79 15.17 130 12.67 16.8 7.885.33 8.64 13.23 39.98 25 14.98 15.49 145 41.3 13.67 10.94 5.36 2.55 4.869.2 60.16 52.4 7.76 11.78 145 17.7 14.67 8.01 4.35 1.36 2.89 6.31 71.0253.9 17.12 10.04 145.5 12.4 15.67 7.03 3.97 0.91 1.72 5.21 74.75 60.714.05 9.86 145 4.3 16.67 6.45 3.89 0.68 1.65 4.75 76.15 75.4 0.75 9.82143.6 2.6 17.17 5.95 3.71 0.54 0.85 4.39 77.96 77.2 0.76 9.72 145 1final 6.01 3.88 0.52 1.34 4.59 77.14 9.83 ^(a)Sampling time: number ofhours after the end of the formaldehyde addition and reaching reflux atabout 100.5° C. ^(b)From the 12.25 hour sample going forward, this isthe (PTBP + methylol) region ^(c)It may contain other linear resins atwell.

Example 9. Synthesis of sec-butylcalix[8]arenes UsingTetramethylammonium Hydroxide (TMAOH) as the Catalyst

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, overhead addition tank, moisture trap, and condenser wasloaded with 112.7 g para-sec-butylphenol (PSBP) powder (>98%, 0.75 mol)and 100.2 g A-150 (Solvesso™ 150 Fluid). A gentle nitrogen flow wasapplied on the surface of the hot reaction mass and the reactor washeated to about 90° C. When all the PSBP and the A-150 formed a clearsolution, 5.5 g of TMAOH solution (25 wt % in methanol, 0.015 mol) wasadded dropwise at a temperature of 85-90° C., and this temperature washold for 30 minutes. At 90° C., a total of 46.0 g of 48.9 wt %formaldehyde solution (0.749 mol) was added within 16 minutes.

After the formaldehyde addition, the reaction was kept at 90° C. for 1hour. The reaction mixture was then heated to reflux for a total of 12hours. At the end of the reflux, the reaction mass was at about 99° C.

The reaction mass was diluted with 99.7 g more A-150 solvent. Thereactor was then heated and the temperature target was set to 145° C. toremove the water. About 2 hours after the heating was started, thetemperature of the reaction mass reached about 142° C., and was kept at142-145° C. for about 10 hours until a total of 26.8 g of the lowerlayer was removed. The crude reaction mass contained 3.43 wt % PSBP.

The GPC results of the crude reaction mass are shown in FIG. 20.Theoretically, the solid content of the crude reaction mass wascalculated to be 37.7 wt % (assuming all water from formaldehydesolution and produced from the reaction were removed; and all excessformaldehyde was removed). The crude reaction mass contained 3.43 wt %free PSBP (which corresponds to 11.08 g or 9.8 mol % of unreacted PSBP).

The ¹H-NMR results of the crude reaction mass are shown in FIG. 21. Theyields of the cyclic phenolic resins were determined by further analysisof the ¹H-NMR results of the crude reaction mass, using the calculationmethodology discussed in Example 1. It was understood that the ¹H-NMRdoes not allow the quantification of the free monomer content; but theGPC results of the final reaction mass display all components in thereaction mass (with their respective resonances at the picked wavelength(here 280 nm)).

The analysis results of the in FIG. 21 are as follows.

Integrals for calixarene phenolic OH protons (for 0.055 all calixarenes)Integrals for two protons of all methylene bridges 0.130 (cyclic andlinear resins) Integrals for one proton of all methylene bridges 0.065(cyclic and linear resins) Ratio of calixarene phenolic OH protons tothe 0.055/0.065 = 84.6% protons of all methylene bridgesTaking into account the 9.8 mol % unreacted PSBP in the yieldcalculation (i.e., 90.2 mol % of the PSBP had reacted) resulted in acrude calixarene yield of 76.3% (i.e., 84.6%×0.902). That is to say, thetheoretical yield of all cyclic components in this crude reaction masswas 76.3%.

Applying the same calculation for the sec-butylcalix[8]arene providedthe following results.

Integrals for sec-butylcalix[8]arene phenolic 0.051 OH protons Integralsfor two protons of all methylene bridges 0.130 (cyclic and linearresins) Integrals for one proton of all methylene bridges 0.065 (cyclicand linear resins) Ratio of sec-butylcalix[8]arene phenolic OH0.051/0.065 = 78.5% protons to the protons of all methylene bridgesTaking into account the 9.8 mol % unreacted PSBP in the yieldcalculation resulted in a crude sec-butylcalix[8]arene yield of 70.8%(i.e., 78.5%×0.902). That is to say, the theoretical yield ofsec-butylcalix[8]arene in this crude reaction mass was 70.8%. This isclose to the observed isolated yield.

This crude reaction mass obtained above was then cooled to about 80° C.,and was easily filtered through a Buechner funnel. The filter cake wassuccessively washed with a total of 105.4 g of A-150. After drying, theproduct sec-butylcalix[8]arene was obtained in an isolated yield of66.3% (theoretical yield), with an HPLC purity of 99.2% (area % at 281nm), and less than 0.05 wt % free PSBP and less than 0.05 wt % A-150.

As noted above and demonstrated through these examples, it has beendiscovered that calix[8]arenes are obtained in a higher yield and highersolid content, and with a significantly improved purity and selectivity.The use of a nitrogen-containing base as a catalyst assists thisprocess. The purity of calix[8]arenes can be further improved by asimple filtration, without the need for recrystallization.

As a comparison, the conventional process using an alkaline base (suchas sodium hydroxide) as the catalyst in a highly diluted reaction system(e.g., 100 g PTBP reacting with 35 g paraformaldehyde in 600 ml xylenesolvent; see Munch et al., Organic Syntheses 68: 243-46 (1990)) producedwith about 20% solid content, and needed a recrystallization step toremove at least 13% of other calixarene oligomers (e.g., calix[4]areneand calix[6]arene) produced in the crude cyclic reaction product. Theprocess disclosed in this application was able to produce about 33% ormore solid content, with a purity of calix[8]arene of 98% or more(characterized by HPLC analysis; not accounting for the attached solventand the unreacted free phenolic monomers), after a filtration and dryingstep. See Examples 1, 5, and 7. For instance, in Example 7, 550 g PTBPreacting with 220 g formaldehyde in 367 ml A-150 solvent produced about68.2% solid content, with a selectivity for tert-butylcalix[8]arene of95.5% (out of all the formed calixarenes; this was determined byseparating all the formed calixarenes by a preparative columnchromatography, with area-% HPLC at 281 nm). No recrystallization wasneeded.

Example 10. Synthesis of tert-amylcalix[8]arenes UsingTetramethylammonium Hydroxide (TMAOH) as the Catalyst inDiphenylether/Xylene

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, overhead addition tank, moisture trap, and condenser wasloaded with 123.2 g para-tert-amylphenol (PTAP) briquettes (0.75 mol),90.2 g diphenylether (DPE), and 10.2 g xylene. A gentle nitrogen flowwas applied on the surface of the reaction mass and the reactor washeated to about 90° C. When all the PTAP and the DPE/xylene formed aclear solution, 5.5 g of TMAOH solution (25 wt % in methanol, 0.015 mol)was added dropwise at a temperature of 89° C. over the course of 3minutes, and this temperature was held for 75 minutes. At 89° C., atotal of 52.2 g of 49.2 wt % formaldehyde solution (0.86 mol) was addedwithin 25 minutes.

After the formaldehyde addition, the reaction was kept at 90° C. for 1hour. The reaction mixture was then heated to reflux at about 96° C. fora total of 12 hours. At the end of the reflux, the reaction mass was atabout 100° C.

The reaction mass was diluted with 60.1 g DPE and 20.1 g xylene solventmixture. Xylene was added to remove the formed water from the reactionmass to avoid boilovers (due to the high boiling point of diphenyl etheras it cannot form effective azeotropes with water by itself).

The reactor was then heated and the temperature target was set to 145°C. to remove the water. The temperature of the reaction mass was kept at145° C. for a total of 10 hours until a total of 34.5 g of lower layerwas removed. This water layer contained 6.4 wt % formaldehyde, whichcorrelates to 8.6% of the total formaldehyde load. The crude reactionmass contained 1.02 wt % PTAP (which corresponds to 2.6% of the startingload of PTAP).

This crude reaction mass obtained above was then cooled to about 50° C.,and was filtered through a Buechner funnel. The filter cake wassuccessively washed with xylene (a total of 106.2 g), and dried in avacuum oven at 130° C. The final product tert-amylcalix[8]arene wasobtained in an isolated yield of 81.2% (theoretical yield) with an HPLCpurity of 98.8% (area % at 281 nm) and less than 0.05 wt % free PTAP and2.78% DPE.

Example 11. Synthesis of tert-octylcalix[8]arenes UsingTetraethylammonium Hydroxide (TEAOH) as the Catalyst in Hexadecane

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, overhead addition tank, moisture trap, and condenser wasloaded with 154.7 g para-tert-octylphenol (PTOP) briquettes (0.75 mol)and 100.0 g hexadecane. A gentle nitrogen was applied on the surface ofthe reaction mass and the reactor was heated to about 90° C. When allthe PTOP and the A-150 formed a clear solution, 5.5 g of a 40% solutionof TEAOH (40 wt % in water, 0.015 mol) was added dropwise over thecourse of 9 minutes. At 90° C., a total of 55.3 g of 46.8 wt %formaldehyde solution (0.86 mol) was added within 25 minutes.

After the formaldehyde addition, the reaction was kept at 90° C. for 1hour. The reaction mixture was then heated to reflux at about 100° C.for a total of 12 hours. At the end of the reaction, the reaction masswas about 100° C.

The reaction mass was diluted with 70.1 g more hexadecane solvent. Thereactor was then heated and the temperature target was set to 145° C. toremove the water. About 2 hours after the heating was started, thetemperature of the reaction mass reached about 145° C., and was kept forabout 10 hours. The crude reaction mass contained 0.68 wt % PTOP. TheGPC results of the crude reaction mass are shown in FIG. 22.

The ¹H-NMR results of the crude reaction mass are shown in FIG. 23.

This crude reaction mass obtained above was then cooled to about 70-80°C., and was filtered through a Buechner funnel. The filter cake wassuccessively washed with portions of isopropanol (a total of 100.6 g),and dried in the vacuum oven at about 130° C. to result in a producttert-octylcalix[8]arene in an isolated yield of 79.4% (theoreticalyield), with an HPLC purity of 97.0% (area % at 281 nm), and 0.13 wt %free PTOP and 0.13 wt % hexadecane (both determined by GC).

Example 12. Synthesis of para-cumylcalix[8]arenes UsingTetramethylammonium Hydroxide (TMAOH) as the Catalyst

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, overhead addition tank, moisture trap, and condenser wasloaded with 160.1 g para-cumylphenol (PCP) (0.75 mol) and 100.5 g A-150(Solvesso™ 150 Fluid). A gentle nitrogen flow was applied on the surfaceof the hot reaction mass and the reactor was heated to about 90° C. Whenall the PCP and the A-150 formed a clear solution, 5.6 g of TMAOHsolution (25 wt % in methanol, 0.015 mol) was added. At about 90° C., atotal of 70.7 g of 37 wt % formaldehyde solution (0.87 mol, stabilizedwith 10-15% methanol) was added within 17 minutes.

After the formaldehyde addition, the reaction was kept at 90° C. for 1hour. The reaction mixture was then heated to reflux at about 100° C.for a total of 12 hours. At the end of the reflux, the reaction mass wasat about 100° C.

The reaction mass was diluted with 78.9 g more A-150 solvent. Thereactor was then heated and the temperature target was set to 145° C. toremove the water (excess formaldehyde and potentially remainingmethanol). About 94 minutes after the heating was started, thetemperature of the reaction mass reached about 144° C. and was kept forabout 10 hours. The crude reaction mass contained 3.25 wt % unreactedpara-cumylphenol. The GPC results of the crude reaction mass are shownin FIG. 24.

The ¹H-NMR results of the crude reaction mass are shown in FIG. 25.

This crude reaction mass obtained above was then cooled to about 70-80°C., and the obtained slurry was filtered through a Buechner funnel. Thefiltered material was successively washed with a first portion of 105.2g A-150 solvent and a second portion of 78.0 g A-150 solvent, and driedin a vacuum oven at 130° C. The final product para-cumylphenol (113.9 g)was obtained in an isolated yield of 60.6% (theoretical yield) with anHPLC purity of 91.0% (area % at 281 nm) and 0.99 wt % free PCP and lessthan 0.05 wt % A-150 (both determined by GC). The impurities in thefinal product may contain some linear resins as well as calix[6]areneand calix[7]arene.

Example 13. Synthesis of tert-amylcalix[8]arenes UsingTetramethylammonium Hydroxide (TMAOH) as the Catalyst

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, overhead addition tank, moisture trap, and condenser wasloaded with 123.2 g para-tert-amylphenol (PTAP) briquettes (0.75 mol)and 88.6 g A-150 (Solvesso™ 150 Fluid). A gentle nitrogen flow wasapplied on the surface of the reaction mass and the reactor was heatedto about 75° C. Over the course of 3 minutes, 5.5 g of TMAOH solution(25 wt % in methanol, 0.015 mol) was added dropwise. At 90° C., a totalof 51.0 g of 50.4 wt % formaldehyde solution (0.86 mol) was added within7 minutes.

After the formaldehyde addition, the reaction was kept at 90° C. for 1hour. The reaction mixture was set to reflux conditions and wasforcefully heated (e.g., it took about 15 minutes to heat the reactionmixture from room temperature to reach about 100° C. and within 60-120minutes the pot temperature can reach about 111° C.), while allowing thedistillate to return back into the reaction flask. The pot temperaturereached to about 115° C. within 4.5 hours of heating and was held at115° C. for additional 1.5 hours. The crude reaction product contained0.52 wt % free formaldehyde and 8.93 wt % unreactedpara-tert-amylphenol.

The reactor was then heated and the temperature target was set to 145°C. to remove the water. The temperature of the reaction mass was kept at145° C. for a total of 10 hours until the water and excess formaldehydewere distilled out. The 38.5 g of aqueous distillate removed contained2.5 g formaldehyde (which corresponds to 9.74% of the startingformaldehyde).

The crude product tert-amylcalix[8]arene was obtained with an HPLCpurity of 86.0% (area % at 281 nm) and 1.98 wt % PTAP (which correspondsto 3.6% of the starting PTAP). The solid content of the final calixarenereaction mass was determined to be about 60%. The GPC results of thecrude reaction mass are shown in FIG. 26.

This crude reaction mass obtained above was then cooled to about 60-70°C., and was filtered through a Buechner funnel. The filter cake wassuccessively washed with 101.7 g A-150 and dried in vacuum oven at 130°C. to result in a tert-amylcalix[8]arene product in an isolated yield of81.3% (theoretical yield), with an HPLC purity of 99.0% (area % at 281nm), 0.44 wt % free PTAP and 1.17 wt % A-150.

Example 14. Synthesis of tert-amylcalix[8]arenes UsingTetramethylammonium Hydroxide (TMAOH) as the Catalyst andParaformaldehyde as the Aldehyde Source in Diphenylether

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, overhead addition tank, moisture trap, and condenser wasloaded with 123.2 g para-tert-amylphenol (PTAP) briquettes (0.75 mol),27.0 g paraformaldehyde (95%, 0.85 mol), and 88.5 g diphenylether. Agentle nitrogen flow was applied on the surface of the reaction mass andthe reactor was heated to about 68° C. To the reaction suspension, at atemperature of 68-80° C., 5.5 g of TMAOH solution (25 wt % in methanol,0.015 mol) was added dropwise over the course of 3 minutes.

The reaction mixture was then further heated with the temperature targetset to 145° C. to remove the water through the moisture trap, with thegentle nitrogen flow assisting in transporting the water to the trap.The temperature of the reaction mass reached about 143° C. within 41minutes, and was kept for about 5 hours between 143-155° C. The 16.0 gaqueous distillate removed contained 2.4 g formaldehyde (whichcorresponds to 9.4% of the starting formaldehyde).

The crude product tert-amylcalix[8]arene was obtained with an HPLCpurity of 85.1% (area % at 281 nm) and 1.27 wt % PTAP (which correspondsto 2.3% of the starting PTAP). The solid content of the final calixarenereaction mass was determined to be about 60%. The GPC results of thecrude reaction mass are shown in FIG. 27.

This crude reaction mass obtained above was then cooled to about 75° C.,and was filtered through a Buechner funnel. The filter cake wassuccessively washed with portions of 108.1 g xylene and dried in vacuumoven at 130° C. to result in a tert-amylcalix[8]arene product in anisolated yield of 82.6% (theoretical yield), with an HPLC purity of96.5% (area % at 281 nm), 0.09 wt % free PTAP and 3.91% diphenylether.

Example 15. Synthesis of tert-amylcalix[8]arenes Using4-(dimethylamino)pyridine (DMAP) as the Catalyst

A 500 ml round bottom flask, equipped with an overhead stirrer,thermocouple, overhead addition tank, moisture trap, and condenser wasloaded with 123.2 g para-tert-amylphenol (PTAP) briquettes (0.75 mol)and 100.8 g A-150 (Solvesso™ 150 Fluid). A gentle nitrogen flow wasapplied on the surface of the reaction mass and the reactor was heatedto about 90° C. When all the PTAP and the A-150 formed a clear solution,1.8 g 4-(dimethylamino)pyridine (0.015 mol) was added at about 93° C.,and the temperature was held for 46 minutes. At about 73° C., a total of55.9 g of 45.9 wt % formaldehyde solution (0.85 mol) was added within 17minutes.

After the formaldehyde addition, the reaction was kept at 90° C. for 1hour. The reaction mixture was then heated to reflux at about 99° C. fora total of 12 hours. At the end of the reaction, the reaction mass wasat about 99° C.

The reaction mass was diluted with 50.1 g more A-150 solvent. Thereactor was then heated to distillation conditions with the temperaturetarget set to 145° C. to remove the water. The temperature of thereaction mass was kept at 145° C. for about 10 hours until a lower layerof 35.4 g was removed, which contained 11.6 wt % formaldehyde (whichcorresponds to 16.0% of the starting formaldehyde). The crude reactionmass contained 0.85 wt % PTAP (which corresponds to 1.9% of the startingPTAP).

This crude reaction mass obtained above was then cooled to about 74° C.,and was easily filtered through a Buechner funnel. The filter cake wassuccessively washed with 105.0 g A-150 and dried in vacuum oven at 130°C. to result in a tert-amylcalix[8]arene product in an isolated yield of79.9% (theoretical yield), with an HPLC purity of 99.0% (area % at 281nm), 0.18 wt % free PTAP and 0.32 wt % A-150.

Sample Characterization Methods.

The reaction products in above examples were characterized by variousmethods, including ¹H-NMR, GPC, and HPLC.

¹H-NMR spectra was recorded at 500 MHz frequency in δ (ppm) using CDCl₃as internal standard.

Gel permeation chromatography (GPC) was conducted with a three-columnset PLGel 5 μm (500 Å, 100 Å, 50 Å) (column temperature of 40° C.) withthe 99/1 THF/MeOH as the mobile phase and the flow rate at 1.0mL/minute, equipped with a UV detector at 280 nm. The sampleconcentration was 2.5 mg/mL with 50 μL injection volume.

High-Performance Liquid Chromatography (HPLC) was performed on a HewlettPackard 1100 Series HPLC System using Agilent InfinityLab Poroshell 120EC-C18 HPLC columns 3.0×150 mm, 2.7 μm (Agilent Technologies) and a UVdetector set at 281 nm. HPLC grade solvents were used. Samples weredissolved in stabilized chloroform (in ethanol or alkane). To obtain ahigh peak resolution for calixarene compounds with varying ring sizes,particularly from ring size 4 to ring size 8, the following combinationsof solvents, gradients, and flow rates were used:

Flow rate: 0.4 ml/minute

Gradient:

Time (min) % C % D  0 90 10  5 90 10 20 80 20 30 40 60 35 20 80 40 20 8042 90 10 C = 99/1 acetonitrile/glacial acetic acid, D = 12:9:1MeCl₂:MTBE (methyl tert butyl ether):glacial acetic acid

The examples of the synthesis of the calixarene compounds are summarizedin Table 5 below.

TABLE 5 Summary of the examples Crude calixarene Water yield [%, Refluxremoval at “Theoretical” based on Ex. Phenolic Time 140-145° C. solidcontent NMR, No. compound Aldehyde Solvent Catalyst [hours] [hours] [wt%] GC] 1 PTBP formaldehyde A-150 DBU 15 5 57.8 78.7 2 PTBP formaldehydeA-150 TEAOH 12 10 37.5 72.9 3 PTBP para- xylene TMAOH — 10.5 — —formaldehyde 4 PTAP formaldehyde A-150 TMAOH 12 10 45.2 80.3 5 PTOPformaldehyde A-150 TEAOH 12 10 60.8 78.1 6 PTBP formaldehyde diphenylTMAOH 12 8.5 32.7 85.6 ether 7 PTBP formaldehyde A-150 DBU 15.25 6.5 68.2^(c)) — 8 PTBP formaldehyde A-150 TEAOH 12 — — — 9 PSBPformaldehyde A-150 TMAOH 12 10 37.7 76.3 10 PTAP formaldehyde diphenylTMAOH 12 10 — — ether/ xylene 11 PTOP formaldehyde hexadecane TEAOH 1210 — — 12 POP formaldehyde A-150 TMAOH 12 10 — — 13 PTAP formaldehydeA-150 TMAOH 6 10 — — 14 PTAP para- diphenyl TMAOH — 5 — — formaldehydeether 15 PTAP formaldehyde A-150 DMAP 12 10 — — Without filtrationtreatment With filtration/ Crude Selectivity for drying treatmentcalix[8]arene calix[8]arene HPLC Free yield [%, amongst Free purity^(b)) phenolic based on all formed phenolic [%, area monomer Ex. NMR,calixarenes monomer % at [wt %, No. GC] [%] [wt %] 281 nm] by GC] 1 74.895   2.2 — — 2 69.3 95.1 3.82 98.8 <0.05 3 — — 4.92 95.2 0.08 4 78.297.4 1.3 99.3 0.29 5 72.5 92.8 1.4 98.9 <0.05 6 83.8 97.9 1.13 92.3^(a))0.12 7 — — 2.36 95.5^(d)) — 8 — — — — — 9 70.8 92.8 3.43 99.2 <0.05 10 —— 1.02 98.8 <0.05 11 — — 0.68 97.0 0.13 12 — — 3.25 91.0 0.99 13 — —1.98 99.0 0.44 14 — — 1.27 96.5 0.09 15 — — 0.85 99.0 0.18 ^(a))with5.1% tert-butylcalix[9]arene ^(b)) HPLC purity of isolated calixarenes^(c))determined experimentally ^(d))isolated by preparative columnchromatography

We claim:
 1. A process for the selective synthesis of a calix[8]arenecompound, comprising: reacting a phenolic compound, an aldehyde, and anitrogen-containing base as a catalyst, in the presence of an organicsolvent; and heating the reaction mixture at an elevated temperature toremove water from the reaction mixture and selectively produce acalixarene compound containing at least 70% calix[8]arene.
 2. Theprocess of claim 1, wherein: the reacting step is carried out underreflux conditions, for a time period of 10 hours or longer; and theheating step is carried out at an elevated temperature of about 140° C.to about 180° C. for a time period of 4 hours or longer.
 3. The processof claim 1, wherein the heating step at the water removal stage iscarried out over a time period of 6 hours or longer to selectivelyproduce a calixarene compound containing at least 90% calix[8]arene. 4.The process of claim 1, wherein the elevated temperature at the waterremoval stage ranges from about 140° C. to about 150° C.
 5. The processof claim 1, wherein the phenolic compound is phenol, an alkyl phenol, oran arylalkyl phenol.
 6. The process of claim 5, wherein the phenoliccompound is a para-C₁-C₂₄ alkyl phenol, benzyl phenol, or cumyl phenol.7. The process of claim 1, wherein the aldehyde is formaldehyde orparaformaldehyde.
 8. A process for a one-step, selective synthesis of ahigh-purity calix[8]arene compound, comprising: reacting, in a one-stepprocess, a phenolic compound and an aldehyde in the presence of a basecatalyst to form a high-purity calix[8]arene compound, without carryingout a recrystallization step.
 9. The process of claim 8, furthercomprising: filtrating the reaction product and drying the filtratedreaction product, thereby producing a calix[8]arene compound with apurity of about 95% or higher.
 10. The process of claim 8, furthercomprising: filtrating the reaction product and drying the filtratedreaction product, thereby producing a calix[8]arene compound with apurity of about 98% or higher.
 11. The process of claim 8, wherein thephenolic compound is an alkyl phenol, an alkyl phenol, or an arylalkylphenol.
 12. The process of claim 11, wherein the phenolic compound is apara-C₁-C₂₄ alkyl phenol, benzyl phenol, or cumyl phenol.
 13. Theprocess of claim 8, wherein the aldehyde is formaldehyde orparaformaldehyde.
 14. A process for the selective synthesis of acalix[8]arene compound with a low free phenolic monomer content,comprising: reacting a phenolic compound and an aldehyde in the presenceof a base catalyst, and washing the reaction product to remove freephenolic compound monomers, to produce a calix[8]arene compound with afree phenolic monomer content of about 0.5% or lower, wherein theprocess does not include a recrystallization step.
 15. The process ofclaim 14, wherein the free phenolic monomer content is about 0.1% orlower.
 16. The process of claim 14, further comprising: filtrating thewashed reaction product and drying the filtrated reaction product,thereby producing a high-purity calix[8]arene compound with a purity ofabout 95% or higher.
 17. The process of claim 14, wherein the phenoliccompound is an alkyl phenol, an alkyl phenol, or an arylalkyl phenol.18. The process of claim 17, wherein the phenolic compound is apara-C₁-C₂₄ alkyl phenol, benzyl phenol, or cumyl phenol.
 19. Theprocess of claim 14, wherein the aldehyde is formaldehyde orparaformaldehyde.
 20. A phenolic oligomer composition prepared by theprocess of claim
 1. 21. A phenolic oligomer composition prepared by theprocess of claim
 8. 22. A phenolic oligomer composition prepared by theprocess of claim 14.